Systems and methods for denoising physiological signals during electrical neuromodulation

ABSTRACT

Systems and methods are described for denoising, or filtering out, unwanted noise or interference, from biological or physiological parameter signals or waveforms such as ECG signals caused by application of electromagnetic energy (e.g., electrical stimulation) in a vicinity of sensors configured to obtain the biological or physiological parameter signals.

PRIORITY APPLICATIONS

This application is a continuation of International PCT Application No.PCT/US2020/031358 filed May 4, 2020, which claims priority to U.S.Provisional Application No. 62/843,772, filed May 6, 2019, the entirecontent of each of which is incorporated herein by reference.

FIELD

The present disclosure relates generally to methods and systems fordenoising (e.g., removing unwanted noise or interference) from a displayof a physiological signal (e.g., bio-signals obtained from ECG, EEG, EKGsensors). Such denoising may be performed during application ofelectromagnetic energy (e.g., electrical stimulation of nerves). Thefield also relates to methods and systems for facilitating electricalstimulation of one or more nerves in and around the heart or otherorgans or tissue without significantly affecting normal operation ofpatient monitors (e.g., during times when electrical stimulation is notbeing applied).

BACKGROUND

Acute heart failure is a cardiac condition in which a problem with thestructure or function of the heart impairs its ability to supplysufficient blood flow to meet the body's needs. The condition impairsquality of life and is a leading cause of hospitalizations and mortalityin the western world. Treating acute heart failure is typically aimed atremoval of precipitating causes, prevention of deterioration in cardiacfunction, and control of the patient's congestive state.

It is also desirable that monitoring of patient vital signs occurs toensure patient safety. Conventional patient monitors utilize one or moresensors with wires connecting the monitor to the patient.

SUMMARY

Patients in intensive care units (ICUs) or critical care units (CCUs)may require continuous monitoring of ECG and frequently otherphysiologic signals (such as invasive or non-invasive blood pressures,pulse oximetry, respiration, or CO₂ levels, among others). These signalsare processed through their respective electronic signal channels in thepatient monitor and may have differing amounts of time delay or latencyas each signal undergoes different types of signal processing. Anydifferences in time delays among the signals are accounted for andcorrected so the signals all align correctly once they are displayed onthe patient monitor.

One approach to removing or reducing the stimulation artifacts is byadding additional filtering to the ECG signals prior to the ECG signalsentering the patient monitor. This may be a viable approach in somecircumstances, but any signal filtering applied external to the patientmonitor will introduce some amount of time delay that results in thedisplayed ECG trace being misaligned with the other displayedphysiologic signals. Small amounts of delay may be unnoticeable on thedisplay, but larger delays will cause a noticeable ECG misalignment withrespect to the other signals and potentially cause confusion ormisinterpretation of a patient's condition. Typically, the moreextensive or complex the filtering applied, the greater the resultingsignal latency and the greater the onscreen misalignment of the ECGtraces.

In some configurations, pre-filtering may include application of a notchfilter or adaptive filter adapted to filter out 50 Hz and/or 60 Hz noise(e.g., typical 50 Hz and/or 60 Hz, 50 Hz-60 Hz, or other line frequencycomponents) from the ECG signals or other biosignals. The pre-filteringmay advantageously provide smoothing of the signals to which a denoisingprocess (e.g., blanking and filtering) is to be applied.

If stimulation parameters such as frequency, amplitude, charge andrecharge pulse widths, and waveform morphology are fixed, it may bepossible to design filters with acceptable performance to satisfy boththe artifact attenuation and latency requirements because these filterscan be tailored to very specific signal characteristics. However, in anactual application these parameters are not always fixed, and the signalcharacteristics are not always predictable. For example, the stimulationartifact amplitude imposed on the ECG signal is not always predictableor even within known bounds. Most filters will either degrade or becomeineffective if the ratio of artifact to ECG amplitude exceeds thecapability of the filter. This is especially true if the artifactamplitude saturates the ECG signal channel, which may happenperiodically.

ECG waveforms on patient monitors can be viewed and interpreted byqualified medical staff or automatically processed by algorithms in thepatient monitors to identify, or detect, specific features orcharacteristics of the waveform. One basic extracted characteristic isheart rate. Others may be detection of certain cardiac arrhythmias thatwill automatically trigger alarms if they occur. For example,ventricular tachycardia or ventricular fibrillation can be deadlyarrhythmias that require immediate intervention by the medical staff.They rely on the arrhythmia detection capability of the patient monitorsto alert them to these conditions.

Patient monitors are used to provide feedback to clinicians regardingreal-time patient health. The patient monitors are configured to displayoutput relating to real-time physiological parameters or vital signs ofthe patient. Clinical professionals monitor the display output todetermine the current status of the patient's health and to diagnosecurrent patient conditions. In addition to visual display, the patientmonitors may also be configured to generate audible output (e.g.,alarms) if a particular physiological parameter or vital sign beingmonitored falls outside a threshold range to alert the clinicalprofessionals of an unsafe condition that may require medical assistanceor attention.

One example of a physiological parameter that is commonly monitored anddisplayed on patient monitors is heartbeat. The heartbeat may bedisplayed on a patient monitor as an electrocardiograph, orelectrocardiogram, waveform (ECG or EKG) that is indicative of theelectrical activity in the heart. The ECG waveform can be monitored byclinical professionals to determine whether any deviations orabnormalities occur that may be indicative of an unsafe and potentiallylife-threatening condition (e.g., atrial fibrillation, ventriculartachycardia, heart disease, cardiac arrest) that may require immediatemedical attention or therapeutic treatment. The ECG waveform can be usedto evaluate heart rate, rhythm, and other cardiac abnormalities and tomake diagnoses.

Accordingly, it is desirable that the ECG waveform that is displayed onthe patient monitor is clean and uncorrupted so as not to generate falsealarms or prompt medical treatment that is not warranted and may causeharm to the patient. In addition, a clean ECG can ensure accuratediagnosis of patient conditions. The ECG waveform is obtained frommultiple sensors (e.g., electrodes or leads) positioned on a skin of apatient at various locations on a patient's body (e.g., on chest, torso,neck, back, legs, and/or arms). The sensors transmit the heart'selectrical activity to a ECG processing device or system. The ECGprocessing device or system generates a waveform or other outputrepresentative of the heart's electrical activity for display (e.g., ona patient monitor).

Unfortunately, the presence of electromagnetic energy generated fromother electromagnetic energy sources in the vicinity of the ECG sensorscan cause unwanted interference or noise to appear on the ECG waveformdisplayed on the patient monitor, especially if the frequency content ofthe ECG waveform, (e.g., electrical signals generated by the heart)and/or other interfering source overlap. This interference or noise cancause the clinical professionals, who are trained to be wary of anyabnormalities on the ECG signal, to be alarmed and can render the ECGsignals difficult or impossible to read, decipher or interpret. Inaddition, the interference or noise may cause automated “false” alarmsor alerts to be generated because the interference or noise may causethe parameters being monitored to fall outside of a normal, expectedcondition or threshold range of values. The increase in false alarms mayresult in alarm fatigue.

One source of interference or noise on the ECG waveform can be a tissuemodulation system configured to provide electrical modulation (e.g.,electrical stimulation) to one or more nerves in and around a heart of apatient or to one or more nerves in and around vessels surrounding theheart (e.g., pulmonary arteries, pulmonary veins) to treat patients withacute decompensated heart failure. For example, catheters havingstimulating elements (e.g., electrodes) may be temporarily inserted intoor externally adjacent vessels surrounding the heart or into chambers ofthe heart to deliver electrical stimulation (e.g., electrical current orelectrical pulses) to stimulate nerves (e.g., autonomic nerve fiberssurrounding a pulmonary artery). These catheters may also causeinterference or noise on the ECG waveform or signal when stimulation isbeing applied. In some implementations, implantable stimulators (e.g.,pacemakers implanted in the heart), fluorescent lights in the vicinityof the patient, or other electromagnetic energy-emitting devices orstructures (e.g., 50 Hz and/or 60 Hz line, 50 Hz-60 Hz, or other linefrequency noise sources, magnetic resonance imaging machines, speakers)may be the source of interference on ECG waveforms when electricalstimulation (e.g., neurostimulation) is being applied.

In addition to being used in connection with neuromodulation (e.g.,neurostimulation) systems for treatment of patients with acutedecompensated heart failure, other applications can also benefit fromseveral of the denoising techniques and systems described herein. Forexample, the denoising techniques and systems may be used in conjunctionwith systems adapted to perform any one or more of the following: spinalneuromodulation, pacing with a pacemaker, defibrillation with animplantable defibrillator or external defibrillation system, pulsedelectrocautery, stimulation of nerves to treat urinary or fecalincontinence, muscle stimulation, prostate stimulation, brain and otherneurological stimulation, stimulation of the vagus nerve, stimulation ofosteoblasts, joint stimulation therapy to treat orthopedic conditions,iontophoresis, stimulation to determine tissue contact,electroanatomical mapping, other non-cardiac related functions, etc.

Methods of addressing the issue of electromagnetic energy (e.g.,neurostimulator) device interference may vary depending on multiplefactors. Most devices can be temporarily turned off in order to recordshort duration ECGs. Other procedures (such as imaging,electrophysiological, or ergometry) may require the devices to beinactivated for longer periods if this is tolerable for the patient.Some devices may be left operational if their stimulation artifacts(e.g., noise or interference on the ECG waveform caused by an electricalstimulation device or system) can be attenuated sufficiently byfiltering within the front-end ECG instrument or system (e.g., low passfilters, band pass filters, notch filters, or other filters).

Several examples of the present disclosure provide for systems andmethods of denoising (e.g., removing noise or interference from) aphysiological parameter signal or waveform (e.g., biopotential,bio-signal, ECG, EKG) in real time (e.g., with minimal latency of lessthan 100 ms). The noise or interference may be caused for example, byapplication of electrical stimulation energy in the vicinity of thesensors (e.g., electrodes or leads) that are acquiring the physiologicalparameter signal (e.g., stimulation artifact). The denoising system mayreceive the signals from the ECG sensors. If electrical stimulation isnot being applied, then the denoising system may be bypassed and notperform any denoising methods, algorithms or processes and the ECGwaveform may be output for display (e.g., directly to a patient monitoror indirectly through telemetry units that transmit the ECG waveform toother display devices and/or central monitoring stations) as normal soas to advantageously affect (e.g., corrupt or impact) the ECG waveformas little as possible to improve fidelity. If electrical stimulation orother modulation is being applied (e.g., as determined by the denoisingsystem from a signal or by automated processing algorithms ortechniques), then the denoising system performs algorithms, methods, ortechniques to remove the noise or interference caused by the electricalstimulation or other modulation (e.g., stimulation artifact) before theECG waveform is output for display.

In some examples, the denoising system comprises, or alternativelyconsists essentially of, a filter subsystem or assembly configured tocommunicate with ECG leads configured to monitor a subject. The filtersubsystem may comprise a digital signal processing system that isconfigured to produce a noise-filtered signal including the signals fromthe ECG leads minus noise from the neuromodulation system and send thenoise-filtered signals to the patient monitor, or to a centralmonitoring system or other display via a telemetry unit (e.g.,wirelessly). For example, the filter subsystem may include a filteradapted to remove 50 Hz and/or 60 Hz, 50 Hz-60 Hz, or other linefrequency components from the ECG signal prior to and/or after othersteps of a denoising process are performed in order to improve fidelityand accuracy of interpolation techniques performed during the denoisingprocess. The denoising system may alternatively include one or moreanalog stages (e.g., unity gain amplifiers, sample-and-hold circuitry)to process ECG signals in an analog domain instead of a digital domain.

In some implementations, an apparatus for removing a transitory noise(e.g., temporary or transient noise) from a digitized biopotential(e.g., ECG waveform or signal) of a living being (e.g., human or animal)is provided. The transitory noise may be generated synchronous withelectrical stimulation of a portion of a body (e.g. heart or vesselssurrounding the heart, such as a pulmonary artery or vein) of the livingbeing. The apparatus includes one or more processors configured to, uponexecution of instructions stored on a non-transitory computer-readablemedium, receive a synchronization signal (e.g., blanking pulse signal)from an electrical stimulation system (e.g., neurostimulator) indicativeof timing of the electrical stimulation, remove the transitory noisefrom the digitized biopotential based upon the received synchronizationsignal, and interpolate across a gap created in the digitizedbiopotential to create a digitized biopotential free (or substantiallyfree) of transitory noise. The transitory noise may only be removedduring the synchronization signal (e.g., while the synchronizationsignal is indicative of electrical stimulation being applied to theportion of the body). In some implementations, the transitory noise isremoved for a time corresponding to 0 to 5 (e.g., 1-5) millisecondsbefore until 0 to 5 (e.g., 1 to 5) milliseconds after receipt of thesynchronization signal (e.g., due to time lag or delay). Interpolatingacross the gap may involve use of one or more of a linear, curvilinear,or cubic spline interpolation approach. Interpolation may includereplacing removed data points or modifying existing data points with newvalues. For example, the interpolation may be based on known good valuesprior to and/or after the time period for which transitory noise isbeing removed from the digitized biopotential.

In accordance with several implementations, an apparatus for removingtransitory noise from a biopotential (e.g., ECG waveform) of a livingbeing is configured to receive a synchronization pulse from anelectrical stimulation system indicative of timing of the electricalstimulation and remove said transitory noise from the biopotential basedupon the received synchronization pulse using an analog-based approach.For example, a unity gain amplifier (or amplifier with other gainvalues) may be applied to the biopotential (e.g., ECG waveform) and avoltage level of the ECG waveform (or signal(s) thereof) may be sampledand held during the synchronization pulse (e.g., while thesynchronization pulse is in a state indicative of stimulation beingapplied by the electrical stimulation system).

In accordance with several implementations, a denoising system isprovided for denoising an ECG signal comprising transitory noise causedby application of electrical stimulation by an electrical stimulationdevice. The denoising system is (or is configured to be) communicativelycoupled to an ECG electrode array (e.g., a plurality of ECG electrodesor sensors) configured to obtain ECG signals from a patient. Thedenoising system includes one or more processors (e.g.,microcontrollers, signal processing circuitry) configured to, uponexecution of stored instructions on a non-transitory computer-readablemedium, detect portions of the ECG signal comprising the noise, anddenoise the detected portions of the ECG signal comprising the noise. Inthis implementation, denoising the detected portions of the ECG signalincludes blanking the detected portions of the ECG signal comprising thetransitory noise (e.g., during a determined “blanking window”) andmodifying (e.g., reconstructing, interpolating) the blanked portions toproduce a reconstructed ECG signal with reduced noise (e.g., free orsubstantially free of noise).

The one or more processors may be further configured to digitize thedetected portions of the ECG signal comprising the noise. The one ormore processors may be further configured to refine the reconstructedECG signal using filtering in the digital or analog domain, such as alinear phase filter (e.g., a 40 Hz low pass filter, a band pass filter),a finite impulse response (FIR) filter, an infinite impulse response(IIR) filter, a Butterworth filter, and/or a Chebyshev filter to createa denoised ECG signal. In some implementations, the one or moreprocessors are further configured to output the reconstructed ECG signalor the denoised ECG signal for display. In some implementations, the oneor more processors are further configured to convert the denoised ECGsignal into an analog signal to facilitate output on a display. Thesystem may include a patient monitor comprising a display configured todisplay the output. The system may further include the ECG electrodearray. The denoising system may comprise a fully integrated systemcomprising the electrical stimulation device, the patient monitor orother display, and/or the ECG front end system (e.g., ECG electrodearray, leadwires, discrete electrical components and/or integratedchips) in addition to the components performing the denoising or maycomprise a separate system configured to connect to the electricalstimulation device, patient monitor or display, and/or ECG front endsystem. In some implementations, the blanking step includes temporarilyremoving values stored at memory locations corresponding to the detectedportions of the ECG signal comprising the noise and the modifying (e.g.,reconstructing, interpolating) step includes calculating modified valuesto replace the removed values in the memory locations. For example, themodified values may be based, at least in part, on known good valuesobtained at memory locations of the ECG signal prior to and/or after theportion of the signal being blanked (e.g., before and/or after theblanking window). In some implementations, the blanking step includesdecimating the detected portions of the ECG signal to remove data points(e.g., using down-sampling techniques) and then re-inserting data pointsduring the modifying (e.g., reconstructing, interpolating) step.

In accordance with several implementations, a system for denoising anECG signal comprising transitory noise caused by application ofelectrical stimulation by an electrical stimulation device includes oneor more processors (e.g., microcontrollers, signal processing circuitry)configured to be communicatively coupled to an ECG electrode array(e.g., a plurality of ECG electrodes or sensors) configured to obtainECG signals from a patient, the one or more processors configured to,upon execution of stored instructions on a non-transitorycomputer-readable medium, detect portions of a digitized ECG signal thatcomprise noise, and denoise the detected portions of the digitized ECGsignal that comprise the noise. Denoising the detected portions of thedigitized ECG signal can include blanking the detected portions of theECG signal having the noise by temporarily removing values at memorylocations corresponding to the detected portions of the ECG signalhaving the noise and replacing the removed values with modified valuesdetermined by modifying (e.g., reconstructing, interpolating) thedetected portions of the digitized ECG signal comprising the noise toreconstruct the ECG signal as a denoised ECG signal with reduced noise(e.g., free or substantially free of transitory noise. The one or moreprocessors are further configured to convert the denoised ECG signal toan analog signal using a digital-to-analog converter to facilitatedisplay of the denoised ECG signal on a display.

The system may further include a patient monitor including the display.The system may also include the ECG electrode array and/or a front-endECG monitoring system or hub. The one or more processors may optionallybe further configured to refine the denoised ECG signal by applyingfurther filtering to smooth out the denoised ECG signal (e.g., using a50 Hz and/or 60 Hz or 50 Hz-60 Hz notch filter, a Butterworth notchfilter or an adaptive noise cancellation filter to minimize signallatency that can be added by a more traditional linear time-invariantfilter completely in series with the signal path) to remove 50 Hz, 60Hz, 50 Hz-60 Hz, or other line frequency noise to smooth out ECG signalsprior to and/or after blanking and/or modification (e.g.,reconstruction, interpolation). The optional further filtering may beperformed in the digital and/or analog domain and may includeapplication of a linear phase filter (e.g., a low pass filter, a bandpass filter, a notch filter), an FIR filter, an IIR filter, aButterworth filter (e.g., Butterworth notch filter), and/or a Chebyshevfilter. A digital FIR or IIR filter may be used that has a linear phaseresponse but that is not a classical linear time-invariant analogfilter. In some implementations, the ECG electrode array or front-endECG monitoring system includes a band pass filter to refine the denoisedECG signal such that the separate optional further filtering is notrequired.

In accordance with several implementations, a method of denoising aphysiological signal (e.g., a cardiac-related signal (e.g., an ECGsignal, an intracardiac electrogram acquired from leads placed directlyon or near the heart), a blood pressure signal) obtained from a patientthat includes transitory (e.g., temporary or transient) noise caused byapplication of electromagnetic energy by a source of electromagneticenergy (e.g., an electrical stimulation system or device) located withinor adjacent the patient is provided. For example, the source may be aneurostimulator positioned within a vessel (e.g., pulmonary artery orvein) surrounding a heart or within a chamber of a heart. The methodincludes detecting portions of the physiological signal comprising thetransitory noise, blanking the detected portions of the physiologicalsignal comprising the transitory noise, and modifying (e.g.,reconstructing, interpolating) the detected portions of thephysiological signal comprising the transitory noise to reconstruct thephysiological signal as a reconstructed physiological signal. Thedetecting, blanking and modifying (e.g., reconstructing, interpolating)may be performed by one or more processors (e.g., microcontrollers,signal processing circuitry) executing instructions stored on anon-transitory computer-readable medium. The blanking and modifying(e.g., reconstructing, interpolating) may be performed using adigital-based or analog-based approach. The blanking may includetemporarily removing values at memory locations corresponding to thedetected portions of the physiological signal having the transitorynoise and the modifying (e.g., reconstructing, interpolating) mayinclude replacing the removed values during the blanking window withmodified values. For example, the modified values may be based, at leastin part, on known good values of the physiological signal correspondingto times prior to and/or after the blanking window during which blankingis performed. In accordance with at least several embodiments, themethod of denoising may not involve applying wavelet transforms (e.g.,discrete wavelet transforms, quadratic spline wavelets) and may notfilter out only asynchronous noise.

In some implementations, the step of detecting portions of thephysiological signal that comprise the transitory noise is based on asynchronization pulse (e.g., blanking pulse) received from an electricaltissue modulation system that is likely to generate the transitory noiseon the physiological signal. The blanking pulse may be received prior toinitiation of electrical neuromodulation therapy by the electricaltissue modulation system or generally coincident with initiation ofelectrical neuromodulation therapy by the electrical neuromodulationsystem. In some implementations, the blanking pulse is continuously in astate (e.g., “on” state) indicative of therapy being applied for anentire duration of the electrical neuromodulation therapy. The methodmay also include digitizing the portions of the physiological signalhaving the transitory noise using an analog-to-digital converter priorto blanking the detected portions of the physiological signal having thetransitory noise. The method may also include converting the denoisedphysiological signal into an analog signal using a digital-to-analogconverter to facilitate output of the denoised physiological signal on adisplay. In other implementations, the portions of the physiologicalsignal are not digitized and the blanking is performed using ananalog-based approach by passing the signal through a unity gainamplifier (or amplifier with other gain values) and then sampling andholding the voltage at a constant level while the blanking pulse is in astate indicative of therapy being applied. The analog denoised signalmay be output to the display. The display may be a display on a patientmonitor or a central monitoring system of a clinical facility.

In some implementations, the method further includes determining whethera physiological parameter of the physiological signal falls outside of athreshold range and generating an alert if the physiological parameterof the physiological signal falls outside of the threshold range. Themethod may also optionally include refining the reconstructedphysiological signal to smooth out the reconstructed physiologicalsignal to create a denoised physiological signal without the transitorynoise. In various implementations, a quality of signal reconstruction(as defined, for example, by the QSR equation provided herein) of thedenoised physiological signal is greater than 95% (e.g., greater than96%, greater than 97%, greater than 98%, about 99%).

In accordance with several implementations, a method of denoising an ECGsignal comprising transitory noise caused by application of electricalstimulation by an electrical stimulation device includes detectingportions of the ECG signal comprising the transitory noise, removingvalues at memory locations corresponding to the detected portions of theECG signal comprising the transitory noise, and replacing the removedvalues with modified values by modifying (e.g., reconstructing,interpolating) the detected portions of the ECG signal comprising thetransitory noise to reconstruct the ECG signal as a reconstructed ECGsignal. The detecting, removing, and modifying (e.g., reconstructing,interpolating) steps may be performed by one or more processors (e.g.,microcontrollers, signal processing circuitry) executing instructionsstored on a non-transitory computer-readable medium.

The method may further optionally include refining the reconstructed ECGsignal with a filter to smooth out the reconstructed ECG signal tocreate a denoised ECG signal, wherein the filter is a linear phasefilter, a Butterworth filter, an FIR filter, an IIR filter, and/or aChebyshev filter. In some implementations, the method includesamplifying the ECG signal before removing values at memory locationscorresponding to the detected portions of the ECG signal. The method mayalso include obtaining the ECG signal from a subject using at least twoECG leadwires (e.g., single lead/channel having two leadwires,two-channel ECG input having two vectors, single channel ECG with asingle lead, 3 electrodes and 3 leadwires). The step of detecting theportions of the ECG signal including the transitory noise mayadvantageously be based on a blanking pulse signal received from theelectrical stimulation device in some implementations. The method mayinclude digitizing the portions of the ECG signal having the transitorynoise (e.g., portions of the ECG signal during a determined blankingwindow) using an analog-to-digital converter prior to removing values atmemory locations corresponding to the detected portions of the ECGsignal having the transitory noise. The method may further includeconverting the denoised ECG signal into an analog signal using adigital-to-analog converter to facilitate output of the denoised ECGsignal on a display. The method may also include outputting the analogsignal to the display, which could be on a patient monitor or a centralmonitoring system.

In some implementations, the method includes determining whether aphysiological parameter of the ECG signal falls outside of a thresholdrange or is indicative of an abnormal heart rhythm. The method mayinclude generating an alert if the physiological parameter of the ECGsignal falls outside of the threshold range or is indicative of anabnormal heart rhythm, wherein the alert is at least one of an audiblealert and a visual alert. The alert may be configured to terminateelectrical stimulation being provided by the electrical stimulationdevice.

In accordance with several implementations, a method of denoising an ECGwaveform obtained from a patient, wherein the ECG waveform comprisestransitory noise caused by application of electrical stimulation by anelectrical stimulation system located within or adjacent the patient,includes receiving a synchronization pulse from the electricalstimulation system indicative of initiation of stimulation by theelectrical stimulation system and removing the transitory noise from theECG waveform based upon the received synchronization pulse using ananalog-based approach. The analog-based approach may include applying aunity gain amplifier (or amplifier with other gain values) to an inputanalog ECG signal, sampling a voltage level of the input analog ECGsignal at a first time instance corresponding to the receivedsynchronization pulse, and holding at the voltage level until thesynchronization pulse transitions to a state indicative of terminationof stimulation by the electrical stimulation system. The terms“synchronization pulse” and “blanking pulse” may be used interchangeablyherein.

In accordance with several implementations, a system for denoisingphysiological signals indicative of a patient parameter is configured todetermine whether a physiological signal (or at least portions of thephysiological signal) received by the one or more processors comprisestransitory noise. If it is determined that the physiological signalcomprises transitory noise, the system is configured to denoise thephysiological signal (or at least the portions of the physiologicalsignal determined to comprise transitory noise). Denoising thephysiological signal may include removing values in memory locationscorresponding to portions of the physiological signal having thetransitory noise and modifying (e.g., reconstructing, interpolating) theportions of the physiological signal having the transitory noise toreplace the removed values with modified values based on said modifying(e.g., reconstructing, interpolating) to reconstruct the physiologicalsignal as a denoised physiological signal. If it is determined that thephysiological signal (or at least portions of the physiological signal)does not comprise transitory noise caused by application of electricalstimulation by an electrical stimulation device, the denoising system isconfigured to cause the physiological signal (or those portions of thephysiological signal determined not to comprise transitory noise) to beoutput for display without modifying the physiological signal. Thesystem may include one or more processors (e.g., microcontrollers,digital signal processing circuitry) configured to, upon execution ofstored instructions on a non-transitory computer-readable medium,perform the recited steps. In some implementations, some of the stepsmay alternatively be performed using analog circuitry or stages (e.g.,unity gain amplifiers and sample-and-hold circuitry).

The physiological signal may include at least one of: a cardiac-relatedsignal such as an ECG signal or intracardiac electrograms acquired fromleads placed directly on the heart, a blood pressure signal, and arespiratory rate signal. The denoised physiological signal may have aquality of signal reconstruction of greater than 95% (e.g., greater than95%, greater than 96%, greater than 97%, greater than 98%, about 99%).The denoising system may be configured to make the determination ofwhether the physiological signal comprises the transitory noise based ona received blanking pulse signal indicative of application of electricalstimulation by the electrical stimulation device. The blanking pulsesignal may be generated by the electrical stimulation device andtransmitted to the system (e.g., one or more processors of the system)through a physical electrical connection or through a wirelessconnection. In some implementations, the denoising system is configuredto make the determination of whether the physiological signal comprisesthe noise based on characteristics of the physiological signal (e.g.,ECG signal). The modifying (e.g., reconstructing, interpolating) mayinclude use of one or more of: linear, curvilinear, and cubic splineinterpolation. The system may further include an analog-to-digitalconverter configured to digitize the physiological signal and adigital-to-analog converter configured to convert the denoisedphysiological signal into an analog signal. The system may optionallyinclude a linear phase filter configured to smooth out the reconstructedphysiological signal after interpolation. Other non-linear phase filtersmay alternatively be used. The system may also include a patient monitorcomprising a display configured to display the denoised ECG signal. Thesystem may optionally include an alert generation subsystem configuredto generate an alarm event if a characteristic of the physiologicalsignal is outside of a threshold range.

In accordance with several embodiments, a system for denoising an ECGwaveform includes an ECG electrode array configured to obtain ECGsignals from a patient and one or more processors configured to becommunicatively coupled to the ECG electrode array. The one or moreprocessors are configured to, upon execution of stored instructions on anon-transitory computer-readable medium, determine whether an ECG signalreceived from the ECG electrode array comprises transitory noise causedby application of electrical stimulation by an electrical stimulationdevice. If it is determined that the ECG signal comprises transitorynoise caused by application of electrical stimulation by an electricalstimulation device, the one or more processors are configured todigitize the ECG signal using an analog-to-digital converter and denoisethe digitized ECG signal. Denoising the digitized ECG signal may includeremoving values in memory locations corresponding to portions of thedigitized ECG signal having the transitory noise and modifying (e.g.,reconstructing, interpolating) the portions of the digitized ECG signalhaving the transitory noise to replace the removed values with modifiedvalues based on said interpolating to reconstruct the ECG signal as areconstructed ECG signal. The one or more processors are furtherconfigured to refine the reconstructed ECG signal using a linear phasefilter (e.g., a low pass filter, a band pass filter, and a notch filter)to create a denoised ECG signal, convert the denoised ECG signal to ananalog signal using a digital-to-analog converter, and output thedenoised ECG signal for display on a patient monitor. If it isdetermined that the ECG signal does not comprise transitory noise causedby application of electrical stimulation by the electrical stimulationdevice, the one or more processors are configured to cause the ECGsignal to be output for display on the patient monitor without modifyingthe ECG signal. Non-linear phase filters (e.g., a Butterworth filter,and/or a Chebyshev filter) may also be used to refine the reconstructedECG signal.

The denoising system may include a stimulation detection subsystemconfigured to make the determination of whether the ECG signal comprisesthe transitory noise caused by application of electrical stimulation bythe electrical stimulation device. The stimulation detection subsystemmay be configured to make the determination based on a received blankingpulse signal indicative of application of electrical stimulation by theelectrical stimulation device. The blanking pulse signal may begenerated by the electrical stimulation device and transmitted to thedenoising system through a physical electrical connection or a wirelessconnection. The stimulation detection subsystem may be configured tomake the determination based on characteristics of the ECG signal (e.g.,an R-R interval between successive R waves of the ECG signal). Thesystem may include the patient monitor comprising a display. The systemcan optionally include an alert generation subsystem configured togenerate an alert if a characteristic of the ECG signal is out of athreshold range. In some implementations, the denoising system includesone or more switches configured to open and close based on thedetermination of whether the ECG signal received from the ECG electrodearray comprises transitory noise.

In accordance with several implementations, a therapeutic systemincludes an electrical stimulation system configured to apply electricalstimulation to a nerve within or surrounding a vessel adjacent a heartof a patient. The therapeutic system further includes a denoising systemconfigured to remove noise artifact caused by the electrical stimulationsystem from an ECG signal received by one or more ECG leads (e.g.,electrodes and leadwires) coupled to the patient by blanking, modifying(e.g., reconstructing, interpolating), and optionally refining the ECGsignal to construct a denoised ECG signal. The blanking and/orinterpolating may be performed digitally by one or more processors orusing analog circuitry. The therapeutic system also includes aphysiological parameter determination subsystem, the physiologicalparameter determination subsystem including one or more processorsconfigured to, upon execution of stored instructions on a non-transitorycomputer-readable medium determine whether a physiological parameterbeing monitored is outside of a threshold range based, at least in part,on signals indicative of the physiological parameter received from oneor more sensors coupled to or positioned within the patient. When thephysiological parameter determination subsystem determines that thephysiological parameter is outside of the threshold range, applicationof electrical stimulation by the electrical stimulation system isterminated and the denoising system is bypassed. When the physiologicalparameter determination subsystem determines that the physiologicalparameter is within the threshold range, application of electricalstimulation by the electrical stimulation system continues and the ECGsignal is processed by the denoising system. The one or more sensorscoupled to or positioned within the patient may include one or morepressure sensors positioned within a chamber of the heart and/or withina pulmonary artery. The physiological parameter may be heart rate.

In some implementations, when the physiological parameter determinationsubsystem determines that the physiological parameter is outside of thethreshold range, the physiological parameter determination subsystemgenerates a stimulation termination signal to be sent to the electricalstimulation system and/or an alert. The alert may be audible and/orvisible (e.g., output on a display of a patient monitor. The alert mayadditionally or alternatively be transmitted to a central monitoringstation of a patient care facility. In some implementations, the alertis transmitted to a mobile communications device of one or more clinicalprofessionals over a communication network (e.g., wireless network,telecommunications network, paging network, cellular network).

Several embodiments of the invention are particularly advantageousbecause they include one, several or all of the following benefits: (i)removal of unwanted or undesired noise artifact or interference frombiological or physiological parameter signals; (ii) reduced processingor computing times; (iii) deterministic algorithms as opposed topredictive or reactive algorithms; (iv) preservation of fidelity andmorphology of original waveforms; (v) reduction in false alarms or alarmfatigue; (vi) ensured accuracy of patient diagnoses; (vii) increasedpatient safety; (viii) ability to provide continuous treatment andmonitoring for several days; (ix) improved “real-time” behavior(especially in memory) of digital signal processing systems vs. otherdigital techniques given the lag time requirements, and/or (x) simplersolutions due to synchronization.

The methods summarized above and set forth in further detail belowdescribe certain actions taken by a practitioner; however, it should beunderstood that they can also include the instruction of those actionsby another party. Thus, actions such as “positioning an electrode”include “instructing positioning of an electrode.”

For purposes of summarizing the invention and the advantages that may beachieved, certain objects and advantages are described herein. Notnecessarily all such objects or advantages need to be achieved inaccordance with any particular example. In some examples, the inventionmay be embodied or carried out in a manner that can achieve or optimizeone advantage or a group of advantages without necessarily achievingother objects or advantages.

The examples disclosed herein are intended to be within the scope of theembodiments herein disclosed. These and other examples will be apparentfrom the following detailed description having reference to the attachedfigures, the embodiments not being limited to any particular disclosedexample(s). Optional and/or preferred features described with referenceto some examples may be combined with and incorporated into otherexamples.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematically illustrates a system that can be used to applyelectrical stimulation to one or more nerves in and around the heart ofa subject.

FIG. 2 schematically illustrates an example electrocardiograph.

FIG. 3A illustrates an example of an ECG signal when no electricalstimulation is being applied by a stimulation system.

FIG. 3B illustrates an example of an ECG signal when electricalstimulation is being applied by a stimulation system.

FIG. 4 schematically illustrates an example of a denoising system.

FIGS. 5A and 5B illustrate examples of timing diagrams of a blankingpulse signal and a stimulation pulse signal.

FIG. 6 schematically illustrates an example method of denoising an ECGsignal when electrical stimulation is being applied by a stimulationsystem.

FIG. 7A schematically illustrates a bypass signal path and examplesstages of the denoising system.

FIG. 7B schematically illustrates example components of the denoisingsystem.

FIG. 8A schematically illustrates an example ECG waveform uncorrupted byapplication of neurostimulation.

FIG. 8B schematically illustrates an example ECG waveform that iscorrupted by application of stimulation to a portion of a body of aliving subject.

FIG. 8C schematically illustrates the example ECG waveform of FIG. 8Bafter blanking performed by the denoising system.

FIG. 8D schematically illustrates the example ECG waveform of FIG. 8Cafter interpolating and optional refining performed by the denoisingsystem.

FIGS. 9A and 9B illustrate close-up exploded views of portions of thecorresponding ECG waveforms of FIGS. 8A and 8B, respectively.

FIGS. 9C and 9D schematically illustrate the portion of the example ECGwaveform of FIG. 9B after blanking (FIG. 9C) and interpolating andoptional refining (FIG. 9D) performed by the denoising system.

FIGS. 10A and 10B illustrate a normal sinus rhythm ECG waveform duringapplication of neurostimulation without denoising and with denoising,respectively.

FIGS. 11A and 11B illustrate an ECG waveform indicative of bigeminyduring application of neurostimulation without denoising and withdenoising, respectively.

FIGS. 12A and 12B illustrate an ECG waveform indicative of atrialfibrillation during application of neurostimulation without denoisingand with denoising, respectively.

FIGS. 13A and 13B illustrate an ECG waveform indicative of ventricularfibrillation during application of neurostimulation without denoisingand with denoising, respectively.

FIG. 14 is a front view of an example tissue modulation system (e.g.,neurostimulation system).

DETAILED DESCRIPTION

Patient monitors are used to provide feedback to clinicians inhospitals, nursing homes and other patient care facilities regardingreal-time patient health. The patient monitoring devices are configuredto display output relating to real-time physiological parameters orvital signs of the patient. Clinical professionals monitor the displayoutput to determine the current status of the patient's health andpossibly increase the level of medical care given to the patient basedon the current status. The clinical professionals may diagnose patientconditions or illnesses or prescribe treatments based on the monitoredphysiological parameters, biopotentials, or vital signs. In addition tovisual display of textual, numerical, or graphical information or datacorresponding to the physiological parameters, biopotentials, or vitalsigns, the patient monitors may also be configured to generate visual oraudible output (e.g., alerts or alarm events) if a particularphysiological parameter, biopotential, or vital sign being monitoredfalls outside a threshold range (e.g., safety limits) to alert theclinical professionals of an unsafe condition that may require medicalassistance or attention. Accordingly, it can be advantageous to makesure that the physiological parameters (or the output indicative of thephysiological parameters) that are displayed and monitored by thepatient monitors are accurate and reliable to reduce alarm fatigue andensure accurate diagnosis.

Physiological parameters can include heart rate, blood pressure,temperature, or the like. One example of a physiological parameter thatis commonly monitored and displayed on patient monitors is heartbeat.The heartbeat may be displayed on a patient monitor as anelectrocardiograph, or electrocardiogram, waveform (ECG or EKG) that isindicative of the electrical activity in the heart. The ECG waveform canbe monitored by clinical professionals to determine whether anydeviations or abnormalities occur that may be indicative of an unsafeand potentially life-threatening condition (e.g., atrial fibrillation,ventricular tachycardia, heart disease, cardiac arrest) that may requireimmediate medical attention or therapeutic treatment. The ECG waveformcan be used to evaluate heart rate, rhythm, and other cardiacabnormalities and to make diagnoses.

Accordingly, it is desirable that the ECG waveform that is displayed onthe patient monitor is clean and uncorrupted so as not to generate falsealarms or prompt medical treatment that is not warranted and may causeharm to the patient. In addition, ECG waveforms corrupted with noise maycause a practitioner to miss an abnormal event or occurrence (e.g.,arrhythmia) and withhold therapy that should not have been withheld. TheECG waveform is derived from signals or measurements from multiplesensors (e.g., electrodes and/or leads or leadwires) positioned on askin of a patient at various locations on a patient's body. The sensorstransmit the heart's electrical activity to an ECG processing device orsystem. The ECG processing device or system generates a waveform orother output representative of the heart's beats and electrical activityfor display (e.g., on a display of a patient monitor).

Unfortunately, the presence of electromagnetic energy generated fromother electromagnetic energy sources in the vicinity of the ECG sensorscan cause unwanted interference or noise to appear on the ECG waveformdisplayed on the patient monitor, especially if the frequency content ofthe ECG waveform (e.g., electrical signals generated by the heart) andthe other interfering source overlap. This interference or noise cancause the clinical professionals, who are trained to be wary of anyabnormalities on the ECG signal, to be alarmed and can render the ECGsignals difficult or impossible to read, decipher, or interpret. Inaddition, the interference or noise may cause automated “false”arrhythmia alarms or alerts to be generated because the interference ornoise may cause the parameters being monitored to fall outside of anormal, expected condition or threshold range (e.g., safety limits). Theincrease in false alarms may result in alarm fatigue.

One source of temporary, transient, or transitory, interference or noisecan include a tissue modulation system configured to provide electricalmodulation (e.g., electrical stimulation, electrical ablation,electrical denervation) to one or more nerves in and around a heart of apatient or to one or more nerves in and around vessels surrounding theheart (e.g., pulmonary arteries, pulmonary veins) to treat patients withacute decompensated heart failure. Catheters having stimulating elements(e.g., stimulatory electrodes) may be temporarily inserted into, orpositioned externally adjacent, vessels surrounding the heart orchambers of the heart to deliver electrical stimulation (e.g.,electrical current or electrical pulses) to stimulate nerves (e.g.,autonomic nerve fibers surrounding a pulmonary artery). These cathetersmay also cause interference or noise (e.g., stimulation artifact) toappear on the ECG waveform when stimulation is being applied by thestimulating elements of the catheters. The degree of interference variesdepending on the location of the stimulation electrodes and thecharacteristics of the stimulation waveform. As another example,pacemakers or other implantable stimulators implanted near the heart maycause interference (e.g., stimulation artifact) on a display of the ECGwaveform when stimulation (e.g., electrical current or electricalpulses) is being applied.

In addition to being used in connection with neuromodulation (e.g.,neurostimulation) systems for treatment of patients with acutedecompensated heart failure, other applications can also benefit fromseveral of the denoising techniques and systems described herein. Forexample, the denoising techniques and systems described herein may beused in conjunction with systems adapted to perform any one or more ofthe following: spinal neuromodulation, pacing with a pacemaker,defibrillation with an implantable defibrillator or externaldefibrillation system, pulsed electrocautery, stimulation of nerves totreat urinary or fecal incontinence, muscle stimulation, prostatestimulation, brain or other central or peripheral neurologicalstimulation, stimulation of the vagus nerve, stimulation of osteoblasts,joint stimulation therapy to treat orthopedic conditions, iontophoresis,stimulation to determine tissue contact, imaging, electroanatomicalmapping or electrophysiology recordings, ergometry, etc.

FIG. 1 schematically illustrates an example tissue modulation system 100that can be used to apply electrical modulation to tissue (e.g.,including one or more nerves) in and around the heart of a subject thatmay generate interference or noise on an ECG waveform while theelectrical modulation is being applied. In one implementation, thetissue modulation system 100 comprises a cardio pulmonary nervestimulation (CPNS) system that is intended to treat patients in acutedecompensated heart failure. The CPNS system can cause electricalinterference (e.g., stimulation artifact) to appear on biopotentials,such as ECG waveforms on a display that is being monitored by aclinician or practitioner).

In some implementations, the location of the electrodes of the CPNSsystem are intended to be near the heart, which is also the source ofthe ECG signals, and the stimulation waveform of the CPNS system hasfrequency components that overlap that of the ECG signals. Accordingly,the presence of the stimulation artifact on the ECG signals caused bythe CPNS system makes the ECG waveform difficult to accurately interpretby trained practitioners and renders automatic arrhythmia detectionfunctions on ECG patient monitors ineffective.

The tissue modulation system 100 may be configured to deliver nervestimulation as either continuous or intermittent biphasic pulse trainsthrough a catheter placed temporarily in the upper thorax near theheart. Patients receiving therapy are typically treated in intensivecare units (ICUs) or cardiac care units (CCUs) within hospitals and arekept on continuous surface electrocardiogram (ECG) monitoring for up tofive days.

In accordance with several implementations, dealing with CPNS-generatedinterference is more challenging than with other neurostimulator devicesfor several reasons: (1) the neurostimulator provides therapy, and assuch, can't be turned off during patient monitoring, (2) theneurostimulation therapy can be delivered for a long continuous durationof time (e.g., up to five days), while requiring patient monitoring theentire time, (3) the CPNS electrodes can be directly in line with theECG vectors, causing a large amplitude interference artifact, and/or (4)the interference frequency spectrum typically overlaps the ECG frequencyspectrum, thereby precluding the use of ECG instrument filters.

The system 100 comprises a first component 102 and a second component104. The first component 102 may be positioned in a pulmonary artery(e.g., the right pulmonary artery as shown in FIG. 1 , the leftpulmonary artery, and/or the pulmonary trunk). The first component 102may be endovascularly positioned via a minimally invasive, transdermal,percutaneous procedure, for example routed through the vasculature froma remote location such as a jugular vein (e.g., an internal jugularvein, as shown in FIG. 1 ), an axial subclavian vein, a femoral vein, orother blood vessels. Such an approach can be over-the-wire, using aSwan-Ganz float catheter, combinations thereof, etc. In some examples,the first component may be positioned invasively, for example duringconventional surgery (e.g., open-heart surgery), placement of anotherdevice (e.g., coronary bypass, pacemaker, defibrillator, etc.), or as astand-alone procedure. As described in further detail herein, the firstcomponent comprises a neuromodulator (e.g., electrode, transducer, drug,ablation device, ultrasound, microwave, laser, cryotherapy, combinationsthereof, and the like) and may optionally comprise a stent or framework,an anchoring system, and/or other components. The first component 102may be acutely positioned in the pulmonary artery for 24 to 120 hours.In some examples, the first component 102 neuromodulates terminalbranches within the cardiac plexus, which can increase left and/or rightventricle contractility and/or relaxation. The increase in ventricularcardiac output due to the contractility increase may occur without acorresponding increase in heart rate, or may be greater than (e.g.,based on a percentage change) that due to an increase in heart ratealone. In some examples, the first component 102 may be adapted toablate tissue, including nerves, in addition to or instead ofstimulating tissue, such as nerves.

The first component 102 is electrically coupled to the second component104 (e.g., via wires or conductive elements routed via a catheter, forexample as illustrated in FIG. 1 , and/or wirelessly). The secondcomponent 104 may be positioned extracorporeally (e.g., strapped to asubject's arm as shown in FIG. 1 , strapped to another part of thesubject (e.g., leg, neck, chest), placed on a bedside stand, etc.). Insome examples, the second component 104 may be temporarily implanted inthe subject (e.g., in a blood vessel, in another body cavity, in achest, etc.). The second component 104 includes electronics (e.g., pulsegenerator) configured to operate the electrode in the first component102. The second component 104 may include a power supply or may receivepower from an external source (e.g., a wall plug, a separate battery,etc.). The second component 104 may include electronics configured toreceive sensor data.

The system 100 may comprise one or more sensors (e.g., pressure sensor).The sensor(s) may be positioned in one or more of a pulmonary artery(e.g., right pulmonary artery, left pulmonary artery, and/or pulmonarytrunk), an atrium (e.g., right and/or left), a ventricle (e.g., rightand/or left), a vena cava (e.g., superior vena cava and/or inferior venacava), and/or other cardiovascular locations. The sensor(s) may be partof the first component 102, part of a catheter, and/or separate from thefirst component 102 (e.g., electrocardiogram chest monitor, pulseoximeter, etc.). The sensor(s) may be in communication with the secondcomponent 104 (e.g., wired and/or wireless). The second component 104may initiate, adjust, calibrate, cease, etc. neuromodulation based oninformation from the sensor(s). Measurements obtained from the sensor(s)(e.g., pressure sensors) may be used to determine whether a patientcondition is within a “safe” or acceptable range within whichstimulation (and denoising processes) may be applied. Otherwise,stimulation may be halted and the denoising systems may be bypassed toincrease patient safety and reduce processing times and complexity.

The system 100 may comprise an “all-in-one” system in which the firstcomponent 102 is integral or monolithic with the targeting catheter. Forexample, the first component 102 may be part of a catheter that isinserted into an internal jugular vein, an axial subclavian vein, afemoral vein, etc. and navigated to a target location such as thepulmonary artery. The first component 102 may then be deployed from thecatheter.

The system 100 may comprise a telescoping and/or over-the-wire system inwhich the first component 102 is different than the targeting catheter.For example, a targeting catheter (e.g., a Swan-Ganz catheter) may beinserted into an internal jugular vein, an axial subclavian vein, afemoral vein, etc. and navigated to a target location such as thepulmonary artery (e.g., by floating). A guidewire may be inserted into aproximal hub through the target catheter to the target location (e.g.,having a stiffest portion exiting the target catheter distal end) andthe first component 102 as part of a separate catheter than the targetcatheter may be tracked to the target location over the guidewire orusing telescoping systems such as other guidewires, guide catheters,etc. The first component 102 may then be deployed from the separatecatheter. Such systems are known by interventional cardiologists suchthat multiple exchanges may be of little issue. Such a system may allowcustomization of certain specific functions. Such a system may reduceoverall catheter diameters, which can increase trackability, and/orallow additional features to be added, for example because not allfunctions are integrated into one catheter. Such a system may allow useof multiple catheters (e.g., removing a first separate catheter andpositioning a second separate catheter without having to reposition theentire system). For example, catheters with different types of sensorsmay be positioned and removed as desired. The system 100 may besteerable (e.g., comprising a steerable catheter) without a Swan-Ganztip. Some systems 100 may be compatible with one or more of thedescribed types of systems (e.g., a steerable catheter with anoptionally inflatable balloon for Swan-Ganz float, a steerable catheterthat can be telescoped over a guidewire and/or through a catheter,etc.).

FIG. 2 schematically illustrates a portion of an exampleelectrocardiograph, or electrocardiogram, (ECG or EKG) waveform. The ECGwaveform includes P waves, Q waves, R waves, S waves, and T waves, whichare each indicative of different events during a single heartbeat of ahealthy subject (e.g., patient). The P wave represents atrialdepolarization, which causes the left atrium and the right atrium topush blood into the left ventricle and right ventricle, respectively.The flat period until the Q wave, the “PR Segment,” and the start of theP wave to the start of the Q wave is the “PR Interval.” The Q wave, theR wave, and the S wave, together the “QRS Complex,” representventricular depolarization, which causes the right ventricle to pushblood into the pulmonary artery and towards the lungs and which causesthe left ventricle to push blood into the aorta for distribution to thebody. The T wave represents repolarization of the left and rightventricles. The flat period until the T wave is the “ST Segment” duringwhich the ventricles are depolarized, and collectively the QRS Complex,the ST Segment, and the T wave are the “QT Interval.” The durationbetween successive R waves or peaks is the “R-R interval.” Some ECGsalso have a U wave after the T wave. The timing, amplitude, relativeamplitude, etc. of the various waves, segments, intervals, and complexescan be used to diagnose various conditions of the heart.

Electrical modulation (e.g., stimulation) from a tissue modulationsystem (such as the systems described herein) or from otherelectromagnetic energy generating systems or devices (e.g.,radiofrequency energy delivery systems, ultrasound energy deliverysystems, microwave energy delivery systems, laser devices, implantablestimulators, transcutaneous electrical stimulation devices, pacemakers,defibrillators, imaging devices, lighting equipment, electrophysiologyrecording or mapping devices) located in a region near one or more ofthe ECG leads or leadwires may interfere with (e.g., cause distortionof, or noise to appear on) a display of a “clean” true ECG waveform.FIG. 3A illustrates an example portion of a clean ECG waveform when noelectrical stimulation is being applied by a stimulation system, suchthat no interference or noise (e.g., stimulation artifact) is present onthe displayed waveform. FIG. 3B illustrates an example portion of theECG waveform when electrical stimulation is being applied by astimulation system. As can be seen in FIG. 3B, the interference or noisecreated by the stimulation source makes it difficult to distinguish thenormal ECG waveform (e.g., the features indicative of the heart beats)and the noise or interference (e.g., stimulation artifact). In someexamples, the portion of the ECG waveform may be modified to account for(e.g., remove, filter out, suppress, cancel out) such interference ornoise (e.g., stimulation artifact) and display a true, or accurate,portion of the ECG waveform (e.g., high-fidelity waveform withoutcompromising original morphology) even while electrical modulation(e.g., electrical stimulation) is being applied to the patient (e.g., bya neuro stimulation system).

The ECG waveform (e.g., one or more portions of the ECG waveform) couldbe artificially flat-lined or ignored during periods of stimulation andthe clinical professionals could rely on alternative physiologicalparameters or vital signs to ensure patient safety during periods ofstimulation. However, many clinical professionals may not be comfortablewith periods of time in which the true ECG waveform is not beingaccurately displayed. In addition, as mentioned previously, the periodsof artificial flat-lining or “blanking” may cause false alarms to begenerated, causing unnecessary worry or stress to the patient orclinicians, or even prompting spontaneous, unwarranted medical actionthat results in harm, or even death, to the patient. Accordingly,several implementations described herein denoise the ECG waveform bymodifying or replacing ECG waveform values at certain time instancesinstead of zeroing the values out or removing the values at those timeinstances without replacing them with alternative values. Accordingly,the data sets before and after denoising may be the same size.

FIG. 4 schematically illustrates an example treatment and patientmonitoring system 400 that includes a denoising system 405 configured toadvantageously remove (e.g., filter out) the unwanted noise orinterference (e.g., stimulation artifact) generated by a stimulationsystem 410 while preserving the fidelity and morphology of the ECGwaveform that is displayed on a patient monitor or other display device415. The treatment and patient monitoring system 400 includes acontroller or control unit 412 configured to control therapy delivery bythe stimulation system 410 to a living subject (e.g., patient) 402. Thecontroller or control unit 412 may comprise a computing device (e.g.,computer, laptop, tablet, smartphone) that includes one or moreprocessing devices (e.g., microcontrollers) and circuitry configured toexecute one or more stored programs or algorithms (e.g., to generateelectrical stimulation pulses of desired patterns and durations). Thecontrol unit 412 may include a touchscreen display configured to allow auser to provide user input by interacting with graphical user interfacesdisplayed on the screen. The display may also be configured to displaystimulation system data and stimulation therapy data received from oneor more sensors.

The stimulation system 410 may comprise, for example, theneurostimulation systems including catheters with electrode structuresand the like as described herein. Other tissue modulation systems,including for other indications other than treatment of heart failure,are also possible. For example, the denoising techniques and systemsdescribed herein may be used in conjunction with systems adapted toperform any one or more of the following: spinal neuromodulation, pacingwith a pacemaker, defibrillation with an implantable defibrillator orexternal defibrillation system, pulsed electrocautery, stimulation ofnerves to treat urinary or fecal incontinence, muscle stimulation,prostate stimulation, brain stimulation, stimulation of the vagus nerve,stimulation of osteoblasts, joint stimulation therapy to treatorthopedic conditions, iontophoresis, stimulation for tissue contactsensing, electroanatomical mapping, electrophysiology recording, etc.The denoising techniques and systems may also be used on conjunctionwith systems or devices employing motors, pumps, piezoelectricactuators, and/or the like. Interference sources that are synchronizableor periodic may be filterable or denoised using the techniques andsystems described herein.

The stimulation system 410 may be configured to generate a programmablestimulation waveform to be applied to nerves of the subject 402 via oneor more electrodes or other stimulation elements. The stimulation system410 may optionally also include sensors (e.g., sensors on a catheter) tosense pressure (e.g., pulmonary artery pressure and right ventriclepressure) and receive signals indicative of the sensed pressure (asshown schematically in FIG. 4 ). The system 410 may also include sensorsthat directly sense electrical activity, such as cardiac electrograms ornerve activity. As discussed herein, application of electricalstimulation to a subject 402 can affect an ECG reading of the subject402. The subject 402 is also connected to leads or leadwires of an ECGsystem 420 according to standard operation procedure to measure the rateand rhythm of heartbeats. Sometimes, an ECG amplifier (not shown) mayoptionally be used to amplify input signals from the ECG system 420.

The system 400 shown in FIG. 4 includes a denoising system 405 betweenthe ECG system inputs 420 (e.g., electrodes, leads, leadwires, and/orprocessing hub) and the patient monitor 415. Instead of the patientmonitor lead wire set 422 of the ECG system inputs 420 connectingdirectly to the patient 402, the ECG inputs 420 (e.g., two-channel24-bit 800 Hz ECG system inputs converted to a 32-b it unsigned integerraw ECG) are connected to the inputs of the denoising system 415 throughthe patient monitor lead wire set 422 and the patient monitor 415 thenconnects to the lead wire set 424 output of the denoising system 405.The denoising system 405 is configured to capture and manipulate datafrom the ECG system inputs 420 prior to sending such data to an optionalECG amplifier or to the patient monitor 415 for display. In someimplementations, the denoising system 405 comprises one or more filters(e.g., 50 Hz notch filter, 60 Hz notch filter, 50 Hz-60 Hz notch filter,Butterworth notch filter, adaptive filters using microcontrollers) topre-filter typical 50 Hz line and/or 60 Hz line or 50 Hz-60 Hz or otherline frequency component noise (and possibly harmonics) out of the ECGsignals received from the ECG system inputs 420 or other analogfront-end ECG system prior to modification (e.g., reconstruction,interpolation) during the denoising process so that values just prior toand after blanking and/or interpolation are known good values that donot include 50 Hz and/or 60 Hz or 50 Hz-60 Hz noise frequency components(e.g., 50 Hz and/or 60 Hz or 50 Hz-60 Hz or other line artifacts orspikes), thereby further enhancing signal fidelity. The one or morefilters may include a bandpass filter (e.g., linear phasefinite-impulse-response filter with a 3 dB cutoff of 0.05 to 40 Hzconverted to signed 16-bit integers with a dynamic range of ±6.25 mV).The denoising system 405 can execute stored instructions or algorithmsusing one or more processors (e.g., computer circuitry or computingcircuits) to perform a process or set of processing steps for denoisingthe ECG signals or the waveform generated and output for display. Thedenoising system 405 may include two signal outputs, one analog and onedigital. The analog output provides denoised ECG signals to the patientmonitor 415 for display. The analog output may have a unity gain orother gain values. The digital output provides a denoised ECG signal tothe neuromodulation system 405. The denoising system 405 may also detectthe QRS complex of the ECG and pass a corresponding marker to theneuromodulation system 410 for heart rate computation, stimulationsynchronization, and/or other functions. The patient monitor lead wireset 422 could be replaced with other types of lead sets connected toother display and/or processing devices besides patient monitor 415,such as a central monitoring system.

The denoising system 405 can process multiple ECG input channels (e.g.,2, 3, 4, 5, 6, 7, 8, 9, 10 or more than 10 channels) and can supportmultiple ECG configurations. Not all channels are required to be used.In some examples, the stimulation system 410 or the ECG system 420 maycomprise the denoising system 405 (e.g., the denoising system 405 may bea component or subsystem of the stimulation system 410 or the ECG system420). In some implementations, the denoising system 405 is a separate,stand-alone component, or module, from the stimulation system 410 or theECG system 420. The denoising system 405 can inhibit or prevent aneurostimulation waveform and/or the effects of neurostimulation on anECG signal from corrupting an ECG signal, or portions thereof.

The denoising system 405 may receive stimulation timing information ordata (e.g., time during which stimulation is applied) from theneuromodulation system 410 to facilitate the denoising process(es)(e.g., facilitate detection or identification of portions of the ECGsignal or other physiological signal or biopotential that comprise noiseor stimulation artifacts or are likely to comprise noise, such asstimulation artifact). In some implementations, the noise, orstimulation artifact, caused by an electrical stimulation system, forexample, comprises periodic pulsatory type noise as opposed to random orcontinuous types of noise. The stimulation timing information maycomprise a blanking pulse signal (e.g., synchronization pulse signal)502 that is transmitted to the denoising system 405 coincident with theinitiation of electrical stimulation pulses. The pulses of the blankingpulse signal 502 may advantageously be synchronized with the pulses ofthe stimulation pulse signal 504, as shown schematically in FIG. 5A. Thefirst pulse of the blanking pulse signal 502 may indicate to thedenoising system 405 that stimulation is about to begin, or isbeginning, and therefore that the portions of the ECG signalcorresponding to the time after the blanking pulse is received arelikely to have temporary, or transitory, noise or interference (e.g.,stimulation artifact) caused by application of electrical stimulation orother electromagnetic energy or fields and that those portions should bedenoised by the denoising system 405. The blanking pulse may becontinuously delivered (e.g., in a state indicative of an “on” or“active” condition) for the duration of the electrical stimulation(e.g., duration of each pulse cycle occurring during an electricalstimulation treatment period, which could last, for example, for severalminutes, several hours, several days, or several weeks).

The pulses of the blanking pulse signal 502 may be used to identify, ordetect, both the beginning and duration of the pulses of the stimulationpulse signal 504. This is true in principle but may requiremodifications in actual use. For example, it may be necessary in someimplementations for the timing of the leading edge and trailing edge ofthe blanking pulses to be adjusted due to perturbations that lead orfollow the stimulation artifact on the ECG waveform. FIG. 5B shows ablanking pulse signal 502′ with modified leading and trailing edges. Inseveral implementations, the leading edge of the first “on” pulse of theblanking pulse signal 502′ is programmed or configured to occur a shorttime prior to the start of the first “on” pulse of the stimulation pulsesignal 504 to allow for data acquisition and processing time inherent inthe ECG signal path of the denoising system 405 and blanking pulsesignal path. This leading offset value may be fixed as determined by thespecifics of the internal denoising system 405 signal delays oradjustable to accommodate other encountered delay variables. Forexample, various implementations of the denoising system 405 and/orprocess 600, 605 may function best when the leading edges of theblanking pulses precede the leading edges of the stimulation pulses by ashort period of time (e.g., 1-10 ms, 1-5 ms, 6-10 ms, 1 ms, 2, ms, 3 ms,4 ms, 5 ms, 6 ms, 7 ms, 8 ms, 9 ms, 10 ms).

The trailing edge of the blanking pulse signal 502′ may alsoadvantageously extend beyond the trailing edge of the stimulation pulsesignal 504 to account for distortion that may occur to the stimulationartifact as it appears on the ECG waveform. The electrical transferfunction through the body between the implanted stimulation electrodesand the surface ECG electrodes can be complex, resulting in not onlyamplitude changes but in time delays of the stimulation artifact on theECG waveform (e.g., spikes caused by stimulation) with respect to thestimulation pulses. In some implementations, the entire stimulationartifact is delayed (including initiation of the artifact and the endingof the artifact). The time delay at the end of the artifact causes theartifact trailing edge to lag the stimulation pulse trailing edge by asmall amount. If the pulse width of the synchronization pulses (e.g.,blanking pulses) is not extended to compensate for this effect, theentire artifact may not be blanked during the denoising process, therebyallowing some of the artifact spike to “leak” through. As with thesynchronization pulse (e.g., blanking pulse) leading edge, the trailingedge offset may use a fixed value or be adjustable to accommodatevariations in artifact distortion. The adjustable synchronization pulse(e.g., blanking pulse) leading or trailing edges may be implementedeither as manually controlled functions by a user (e.g., based onartifact observed in the baseline of the denoised ECG signal) ordetermined automatically by methods or algorithms within the denoisingsystem 405 or process 600, 605. In accordance with severalimplementations, because the denoising system 405 receives an indicationin advance as to when stimulation is occurring as a result of receipt ofthe stimulation timing information (e.g., synchronization pulse), thedenoising system 405 and processes 600, 605 can advantageously bedeterministic and require less processing speed and/or computingresources. There may also be reduced signal latency compared to priormethods. The denoising processes and methods may be performed in realtime (e.g., with minimal latency of less than 100 ms) such that theclinical professionals do not even realize that the denoising is beingperformed. In addition, the denoising system 405 and processes 600, 605may advantageously not require linear circuit operation during noiseartifact periods which makes it tolerant to signal saturation at thosetimes.

The system 400 shown in FIG. 4 may further optionally comprise aphysiological parameter determination subsystem or module. Thephysiological parameter determination subsystem or module may be anindependent subsystem or module or may be a sub-component of theneuromodulation system 410 or the denoising system 405. Thephysiological parameter determination subsystem or module may beconfigured to, upon execution of instructions stored on acomputer-readable medium by one or more processors, determine whether aphysiological parameter being monitored (e.g., heart rate or othercardiac-related parameter, pressure within a cardiac-related vessel orchamber, such as a pulmonary artery or a ventricle) is outside of athreshold range. The threshold range may correspond to a predeterminedacceptable safe range that does not cause alarm or require medicalattention. The physiological parameter value may be determined based onsignals received from one or more sensors coupled to tissue of a patient(e.g., R-R intervals determined from signals received from ECG leadscoupled to skin of a patient) or positioned within a lumen or cavity ofa patient (e.g., pressure values determined from pressure sensorspositioned within a blood vessel or a heart chamber).

If the physiological parameter determination subsystem or moduledetermines that the physiological parameter is outside the thresholdrange, the physiological determination subsystem or module may cause theneuromodulation system 410 to stop, or terminate, application ofneuromodulation to the patient and may cause the denoising system 410 tobe bypassed so as not to affect the ECG signals that no longer requiredenoising since the neuromodulation has been terminated. In someimplementations, the physiological determination subsystem or modulegenerates a control signal that is sent to the neuromodulation system410 and/or to the denoising system 410. The physiological parameterdetermination subsystem or module may also comprise an alert generationsubsystem or module configured to generate an alert or alarm event whenthe physiological parameter is determined to be out of range. The alertmay be a visual alarm output to a display (e.g., on a patient monitor oron a display of a central monitoring system in a patient care facility).The alert may additionally or alternatively comprise an audible alert oralarm. The alerts may generate a text message, electronic mail message,page, or other warning message to a display of a central monitoringsystem of a health care facility or to a mobile communications device(e.g., pager, smartphone) of one or more individual caregivers. Thealerts may be transmitted through wired connections or wirelessly (e.g.,via Bluetooth or cellular data communication protocols or systems over acommunications network). If the physiological parameter determinationsubsystem or module determines that the physiological parameter iswithin the threshold range, no action is taken and the neuromodulationsystem 410 and the denoising system 405 may continue to operate asnormal.

With reference to FIG. 6 , an example of an algorithm or process 600 ofdenoising ECG signals or waveforms performed by the denoising system 405is schematically illustrated. The denoising system 405 can executestored instructions or algorithms using one or more processors (e.g.,computer circuitry or computing circuits) to perform the process 600. AtBlock 602, the various ECG signals are received directly from the ECGsensors, or from the ECG system inputs 420. At decision Block 604, thedenoising system 405 determines whether stimulation or otherelectromagnetic energy is currently being applied. In accordance withseveral implementations, the process 600 advantageously does not applyfiltering (e.g., blanking and modifying (e.g., reconstructing,interpolating) to the entire ECG waveform. Instead, the process 600applies filtering only to portions of the ECG waveform likely to havestimulation artifacts, thereby leaving those portions that are free (orsubstantially free) of stimulation artifact unaffected and unmodified.In some examples, the denoising system 405 can receive a signal from theneuromodulation system 410 when the neuromodulation system 410 isapplying neurostimulation through a physical electrical connection(e.g., the blanking pulse signal 502 described above). The denoisingsystem 405 may be configured to correlate the time of receipt of thesignal indicative of application of neurostimulation therapy or othermodulation or electromagnetic energy with the timing of the ECG signalsso as to know which portions of the ECG signals comprise, or are likelyto comprise, noise or interference (e.g., stimulation artifacts).

In some implementations, a synchronization blanking pulse signal may notbe used and the determination of whether stimulation is being applied isindependently determined by the denoising system 405 based on ananalysis of the ECG waveform to predict or determine whether stimulationis being applied and/or to generate a synchronization (e.g., blanking)pulse signal, or signal indicative of stimulation being applied. Thesynchronization (e.g., blanking) pulse signal can be generated from thestimulation-corrupted ECG signal directly, thereby eliminating the needfor a separate synchronization pulse (e.g., blanking pulse). Because thestimulation signal, and hence the artifact, are periodic, they can beextracted from the original ECG signal using one or more clockextraction techniques, such as autocorrelation, or by using a phasedlocked loop (PLL). Additional methods can be employed to determine thecorrect blanking pulse width and the optimal phase relationship to usewith the stimulation signal. Once these values are determined they canbe saved and quickly reapplied for successive stimulation pulses. If thestimulation parameters change, the denoising system 405 can once againdetermine the correct denoising parameters to apply. This “extractedblanking pulse” technique could be useful, for example, in circumstanceswhere a denoising function is applied to a system not originallydesigned to provide a synchronized blanking pulse signal.

As another example, a peak detector (e.g., 20 Hz peak detector) could beused in combination with other methods or techniques to detect thepresence of noise caused by the neuromodulation system 410 as anindicator of whether electrical stimulation or other modulation is beingapplied at the current time. In various implementations, differentwireless synch (including optical links), wired synch or synchgeneration techniques may be used. For example, a wireless connectionsuch as Bluetooth or a number of other means can also be used in placeof a physical electrical connection.

If it is determined at decision Block 604 that stimulation is beingapplied, then a denoising sub-process 605 is initiated by the denoisingsystem 405. For example, the blanking pulse signal 502 from theneuromodulation system 410 can open a circuit to interrupt the directconnection between the ECG system 420 and the patient monitor 415 andinstead direct the original corrupted ECG signal to the denoising system405. If it is determined at decision block 604 that stimulation is notbeing applied, then the ECG waveform can be output for display at Block610 as normal without going through the denoising sub-process 605. Whenno signal indicative of stimulation being applied is received from theneuromodulation system 410, the circuit between the ECG system 420 andthe ECG amplifier 425 can be re-closed and the denoising system 405 maybe bypassed. In other words, the ECG signals are not directed throughthe denoising system 405 and are processed without going through theprocessing of the denoising system 405. The denoising system 405 caninclude multiple switches that can be triggered (change the statebetween open and closed) depending on the determination of whether ornot stimulation is being applied (and thus, whether the denoising system405 should be bypassed or not). For example, when the ECG input signalsare bypassing the denoising stages, normally closed switches betweeneach ECG channel input and corresponding channel output can be used topass the ECG signals directly to the output of the denoising system 405without any filtering or signal modification. When the denoisingsub-process 605 is active, the state of the switches may be changed todirect the ECG input signals to the denoising circuitry stages.

In implementations where a blanking or other synchronization pulsesignal is generated, the denoising process 500 may be treated as asystem-level operation because the neuromodulation system 410 not onlygenerates a stimulation therapy signal but also generates thesynchronization pulse signal that facilitates the denoising 600 (e.g.,denoising sub-process 605). Turning briefly to FIG. 7A, an example of abypass path in which at least the major stages of the denoisingsub-process 605 (e.g., ECG analog front-end stage, which may include ananalog-to-digital-converter and/or amplifier, a microcontroller thatperforms the denoising sub-process, and an analog out stage, which mayinclude a digital-to-analog converter and/or amplifier) are bypassed.

Turning back to FIG. 6 , the denoising sub-process 605 may includemultiple processing steps. At Block 606, the portions of the ECGwaveform or signals that are likely to include artifact spikes orinterference noise during stimulation (as determined by, or as detectedor identified based on the stimulation timing information or datareceived from the neuromodulation system 410) may be “blanked” from theECG waveform or signals (e.g., during a determined blanking period orwindow). The components of the denoising sub-process may be performed onall of the portions or components of the ECG waveform or signalsidentified or detected as having noise (e.g., during the duration ofeach stimulation or other modulation pulse cycle) at the same time(e.g., simultaneously) or may be performed on each portion separately(e.g., sequentially).

The denoising sub-process 605 may be performed for the entire length ofstimulation (e.g., the whole time the blanking pulse is in a stateindicative of stimulation being “on” or “active”) or for a portion ofstimulation. The denoising sub-process 605 may or may not be performedduring the time (either all or a portion of the time) of the blankingpulse that occurs prior to actual stimulation. For example, if the firstblanking pulse is received 4 ms prior to actual stimulation, thedenoising sub-process 605 may start after 4 ms or after a time less than4 ms (e.g., 2 ms, 3 ms, 1 ms). In one implementation, the “blanking” mayinvolve application of one or more decimation filters to permanentlyeliminate data points during the time of stimulation (e.g., byperforming down sampling), thereby resulting in a data set that issmaller in size than the original data set. The eliminated data points(e.g., data values and certain memory locations) may not be replaced inthese implementations. However, the decimated data points could bereinserted with new data points whose values are calculated during asubsequent interpolation step. Under this approach, the final data setwould once again be larger and match the size of the original data setprior to decimation. In another implementation, data points at variousintervals (e.g., memory locations) are not permanently eliminated duringthe blanking step but are preserved and values at the data points aremodified or substituted with different values (e.g., value of thepreceding or succeeding memory location, or a mean of the values inpreceding and/or succeeding memory locations, or a value between thevalue in the preceding and/or succeeding memory location) during asubsequent interpolation step. Because the denoising sub-process 605removes the stimulation artifact through blanking, even artifacts thatsaturate the analog channel can be successfully removed or modifiedwithout adversely impacting the underlying ECG waveform. The blankingmay include compressed, saturated, or clipped portions of the ECGsignals. The ECG signals may be digitized prior to or at Block 606 usingdigitizing circuitry, such as an analog-to-digital converter (ADC). Thedigitized ECG signals may also be amplified.

At Block 607, interpolation or other modification or reconstruction maybe performed to fill in the gaps (e.g., insert straight or curved linesegments to connect the dots) created by the blanking performed at Block606. In some implementations, interpolation involves taking a last knowngood value prior to blanking and duplicating that value at all datapoints during the blanking window. The interpolation may involve takingthe last known good value prior to blanking and the first known goodvalue after blanking and interpolating between those two values toinsert interpolated values at data points or memory locations during theblanking. In some implementations, interpolation may simply involveinserting the last known good value prior to blanking and inserting thatsame value in all of the memory locations during the blanking. Ifdecimation was performed in the blanking step, the decimated locations(e.g., data points) could be reinserted with new data points whosevalues are calculated using interpolation filters or techniques. If nodecimation was performed in the blanking step, the values at theexisting data points may simply be replaced using interpolation filtersor techniques. In both implementations, the final data set may be thesame size as the initial data set—the difference being that ifdecimation is performed, new data points are added to replace datapoints removed during decimation (which may involve down-sampling) andif decimation is not performed, no new data points are added).Interpolation filters and digital filtering techniques may be used toperform the interpolation (including finite-impulse-response (FIR)filters or adaptive filters). Interpolation may include up-sampling(e.g., if decimation was performed during the blanking step). Refiningfiltering techniques may then optionally be applied at Block 608 tosmooth out the final waveform (or preserve the general original waveformappearance) for display. In some implementations, refining comprisesapplication of a linear phase filter. In one example, band passfiltering is performed using a linear phase FIR filter with a 3 dBcutoff of 0.05 Hz to 40 Hz and converted to signed 16-bit integers witha dynamic range of +/−6.25 mV. In some implementations, a 40 Hz low passfilter is used. In some implementations, the denoising sub-process 605may involve decomposing the digitized ECG signals into subcomponents indifferent domains (e.g., time domain and frequency domain). The optionaladditional filtering at Block 608 may also include detection of R waves.The R-wave detection may be sent to the neuromodulation system 410. Thesignals may be converted from digital to analog signals at or followingBlock 608 (e.g., using a digital-to-analog converter) and before outputfor display at Block 510.

In some implementations, the filters involved in the denoisingsub-process 605 introduce a slight signal delay (e.g., 5-20 ms, 10-20ms, 15-25 ms, 15-17 ms, overlapping ranges thereof, or any value withinthe recited ranges). Use of an optional digital-to-analog converter mayadd even more latency. In accordance with several implementations, totaldelay and latency is less than 100 ms (e.g., less than 90 ms, less than80 ms, less than 70 ms, less than 60 ms, less than 50 ms, less than 40ms, less than 30 ms, less than 25 ms). The modifications to the timingof the blanking pulse signal 502 described above in connection with FIG.5B may help to account for the latency and delay of the denoisingsub-process 605.

In some implementations, the process 600 includes additionalsub-processes. In some implementations, stimulation or delivery ofelectrical modulation by the neuromodulation system 410 is halted ifmeasured parameters (e.g., R-R intervals or relevant vessel or chamberpressures determined by the pressure sensors of the neuromodulationsystem 410) are determined to be out of the acceptable safe range, andthe denoising sub-process 605 is bypassed. For example, the process 600may include a threshold preliminary sub-process (which may be carriedout by the physiological parameter determination subsystem or moduledescribed above in connection with FIG. 4 ) that analyzes the input ECGwaveform or signals and determines an R-R interval (a single R-Rinterval or an average R-R interval). If the R-R interval is determinedto be too short or too long (e.g., below or above a threshold indicativeof tachycardia, bradycardia, or other abnormal heart rhythm condition),the process 600, via an alert generation subsystem or module, maygenerate a control signal that is sent to the neuromodulation system 410to automatically terminate modulation (e.g., stimulation) for safetyreasons. Alternatively, an alert (e.g., audible, visible alert or alarmevent) could be generated to prompt the clinician to manually terminatestimulation. If the R-R interval is determined to be within anacceptable “safe” range, then the process 600 may continue to thedenoising sub-process 605. Hospital monitors' first level of detectioncan be based on R-R intervals, which are not impacted (not significantlyimpacted) by the denoising processes described herein.

Another optional sub-process that may be performed prior to thedenoising sub-process 605 includes detection of pacemaker pulses on theECG waveform or signals. This sub-process may involve stripping out thepacemaker pulses and reinserting them in the ECG waveform after thedenoising sub-process 605. In some implementations, the process 600 mayinvolve execution of a lead-off detection module or sub-process thattriggers errors that generate a “lead off” condition if impedancemeasurements are outside a threshold range. The errors may result ingeneration of an alert, using an alert generation subsystem or module,that something is wrong that may require attention. In someimplementations, the alerts may include indication of loss of contactbetween a sensor and tissue or between a stimulation electrode of themodulation system 410 and tissue (e.g., based on impedance and/or forcemeasurements) or indication of catheter migration based on a determinedreal-time position of a component (e.g., catheter tip, stimulationelectrode, sensor) of the modulation system 410. Such alerts may bebased on a detection of changes in stimulation artifact characteristics.The various alerts described herein may be audible and/or visible. Thealerts may generate a text message, electronic mail message, page, orother warning message to a display of a central monitoring system of ahealth care facility or to a mobile communications device (e.g., pager,smartphone) of one or more individual caregivers. The alerts may betransmitted through wired connections or wirelessly (e.g., via Bluetoothor cellular data communication protocols or systems over acommunications network). Another sub-process of process 600 may includethe actual treatment of the patient using the neuromodulation system 410by applying electrical stimulation to nerves to treat acute heartfailure.

In some configurations, a pre-filtering sub-process may optionally beperformed prior to or during the denoising sub-process 605. Thepre-filtering sub-process may be performed prior to or during Block 606.The pre-filtering sub-process may include application of a notch filteror adaptive filter adapted to filter out 50 Hz and/or 60 Hz noise (e.g.,typical 50 Hz and/or 60 Hz line frequency or 50 Hz-60 Hz frequencycomponents) from the ECG signals or other biosignals received by thedenoising system 405. The pre-filtering sub-process may advantageouslyprovide smoothing of the signals around the “blanking” window (e.g.,before and/or after the blanking window) to further enhanceinterpolation during the denoising sub-process 605 due to the absence of50 Hz and/or 60 Hz noise artifacts otherwise present on the signals orwaveform during the blanking window. In some implementations, thepre-filtering sub-process comprises application of a moving averagewindow before and/or after the blanking window to smooth out theportions of the signals passed on to the blanking and interpolationsub-processes.

FIG. 7B schematically illustrates example components of the denoisingsystem 405. The denoising system 405 includes one or more input/outputinterfaces, ports, or modules. The input/output interfaces may includeone or more input interfaces 703 and one or more output interfaces 706.The input interfaces 703 may include an ECG lead input interface throughwhich the signals from the ECG system 420 (e.g., including sensors andleads and a processing hub) are received and/or a stimulation timinginput interface through which stimulation timing information or data isreceived from the neuromodulation system 410. The denoising system 405may optionally include a stimulation detector module or subsystem 714that is configured to determine whether stimulation, or othermodulation, is being applied that is causing unwanted interference ornoise (e.g., stimulation artifact) on the ECG waveform. As describedabove, the stimulation detector module or subsystem 714 can detectstimulation based on a received blanking pulse signal or based onanalysis of the ECG signals or waveform without receiving a blankingpulse signal. In some implementations, the blanking pulse signal 502 isreceived from the neuromodulation system 410 as a logic level signal viaa micro USB connector and an optical isolator. The denoising system 405may provide real-time detection of the R-wave and communicate alogic-level signal corresponding to the R-wave peak to theneuromodulation system 410 via the micro USB connector. The denoisingsystem 405 may also include an analog-to-digital converter (ADC) 709that digitizes the received analog ECG signals for signal processingpurposes and a digital-to-analog converter (DAC) 712 that converts theprocessed and filtered digital signals back to analog signals. The ECGanalog front-end stage 70 of FIG. 7A may include one or more of theinput interface(s) 703, the stimulation detector 714, the lead-offdetector 716, and ADC 709. The filter subsystem 715 may include themicrocontroller 713 of FIG. 7A and/or the stimulation detector 714. Theanalog out stage 711 of FIG. 7A may include one or more of the DAC 712and output interface(s) 706.

The denoising system 405 further includes a filter subsystem 715 thatperforms various signal processing functions to remove the noise fromthe ECG waveform. The filter subsystem 715 may include a blankingsubsystem or module and an interpolation subsystem or module, and mayoptionally include additional refining filtering subsystems or modules(such as the pre-filtering subsystems or modules to remove typical 50 Hzand/or 60 Hz line or 50 Hz-60 Hz frequency components prior to blankingand/or interpolation described herein). The blanking subsystem or moduleis configured to, upon execution of instructions stored on anon-transitory computer readable medium, blank selected data values ofselected portions of the digitized signal corresponding to the timeduring which stimulation was, or is being, applied. In someimplementations, the data values at selected memory locations arepreserved and modified to new data values that replace the temporarilyremoved data values during subsequent interpolation. In someimplementations, the blanking subsystem or module is configured toperform decimation, whereby selected data points corresponding toportions of the digitized signal identified as having transitory noise(e.g., stimulation artifact) are eliminated (e.g., down-sampled), andthen perform up-sampling to pad with new data points of selected values.The blanking subsystem or module configured to reduce a sampling rate ofthe digitized ECG signal (e.g., to reduce the computational complexity)to reduce the number of data points during the identified, or detected,stimulation periods in either approach. The blanking subsystem or modulemay perform anti-aliasing filtering and may include a low pass filterwith a particular cutoff frequency. The interpolation subsystem ormodule is configured to fill in the gaps created by blanking during thestimulation periods. For example, in some implementations, theinterpolation subsystem or module captures a last data point (e.g., lastknown good value) prior to blanking and a first data point (e.g., firstknown good value) after the blanking and then interpolates between thesetwo data points. In some implementations, the interpolation subsystem ormodule may duplicate a value of the last known good data point prior toblanking and duplicate that value in all of the data points during theblanking period or window. The interpolation subsystem or module mayincrease the sampling rate of the digitized signal to add back in (e.g.,pad) samples that were removed during decimation or fill in the datavalues at data points that were preserved during blanking with newmodified values based on interpolation in order to make the signal moreaccurate and smooth. The interpolation may include performing one ormore of linear, curvilinear, and cubic spline interpolation, as well asother interpolation techniques.

Although the denoising sub-process 605 (e.g., blanking and interpolatingtechniques) have been described as being implemented in the digitaldomain with digital signal processing techniques, the denoisingsub-process 605 may also be implemented with similarly useful results inthe analog domain. For example, one such approach involves use of aunity gain amplifier (or amplifier with other gain values) and then thedenoising system 405 is configured to sample and hold at a steady orfixed voltage level at the time the blanking pulse signal 502 isreceived and then return to unity gain or other gain value when theblanking pulse signal 502 is no longer being received (e.g., is nolonger in an active state indicative of stimulation being applied). Thetransient that might occur as a result could be filtered to providesmoothing. In accordance with several implementations, a method ofdenoising an ECG waveform obtained from a patient, wherein the ECGwaveform comprises transitory noise caused by application of electricalstimulation by an electrical stimulation system located within oradjacent the patient, includes receiving a synchronization pulse (e.g.,blanking pulse) from the electrical stimulation system indicative ofinitiation of stimulation by the electrical stimulation system andremoving the transitory noise from the ECG waveform based upon thereceived synchronization pulse using an analog-based approach. Theanalog-based approach may include applying a unity gain amplifier (oramplifier with other gain values) to an input analog ECG signal,sampling a voltage level of the input analog ECG signal at a first timeinstance corresponding to the received synchronization pulse, andholding at the voltage level until the synchronization pulse transitionsto a state indicative of termination of stimulation by the electricalstimulation system.

The optional additional refining filtering subsystem or modules mayinclude a linear phase filter (e.g., achieved using a finite impulseresponse filter). The linear phase filter may advantageously makere-creation of the wave shape of the original ECG input signal feasible(e.g., such that morphology of the ECG waveform is not significantlyimpacted by the denoising system 405 and processes). In oneimplementation, band pass filtering is performed using a linear phaseFIR filter with a 3 dB cutoff of 0.05 Hz to 40 Hz and converted tosigned 16-bit integers with a dynamic range of +/−6.25 mV. In oneimplementation, the additional filtering subsystem or modules mayinclude a 40 Hz low pass filter prior to being routed to the denoisingsystem output lead wires 424, thereby providing a connection point tothe patient monitor 415. However, other filters or filtering techniquesin the digital and/or analog domain may be used as desired and/orrequired. For example, a Butterworth filter may be used in certainimplementations. Chebyshev filters or other filters or filteringtechniques (e.g., a Wiener filter, a morphological filter) may also beused as desired and/or required. In some implementations, no additionalfiltering is required after interpolation or other modification orreconstruction. For instance, the ECG monitoring systems may itselfinclude a band pass filter on the front end that can eliminate anyresidual transitory noise (e.g., stimulation artifact) followinginterpolation. The additional filtering subsystem or module may includea notch filter or adaptive filter to remove 50 Hz and/or 60 Hz or 50Hz-60 Hz frequency components or noise prior to blanking and/orinterpolation.

The denoising system 405 may also include a lead-off detector module orsubsystem 716 configured to monitor contact impedance measurements anddetect when one of the ECG leads is not properly attached or connected(and thus not generating accurate data) based on the monitored contactimpedance measurements. The denoising system 405 may further include apower supply 718 adapted to power the components of the denoising system405. The power supply 718 may include a battery, capacitor, or otherenergy storage device. The power supply 718 may be rechargeable.

FIGS. 8A-8D help schematically illustrate the effects on the ECGwaveform at various steps of denoising processes, such as thosedescribed herein. FIG. 8A illustrates an example clean ECG waveformwithout any noise (e.g., when electrical stimulation is not beingapplied). FIG. 8B illustrates the same ECG waveform but at a time duringelectrical stimulation when the noise or interference caused by theelectrical stimulation (e.g., stimulation artifact) is visible on theECG waveform. FIG. 8C schematically illustrates the ECG waveform of FIG.8B after a blanking step is performed by the denoising system 405. Ascan be seen in FIG. 8C, the spikes caused by the stimulation have beenremoved from the ECG waveform. FIG. 8D schematically illustrates theexample ECG waveform of FIG. 8C after interpolating and additionalfiltering steps are performed by the denoising system 405.

The accuracy of the blanking and interpolation steps of the denoisingsub-process 605 are illustrated better with a zoomed-in view of theportions of the waveforms with the stimulation artifact. FIGS. 9A-9Dillustrate close-up, exploded views of a portion of the correspondingECG waveforms of FIGS. 8A-8D. The portion of the ECG waveforms in FIGS.9A-9D is the portion indicated by the rectangle overlaid over thewaveform toward the right end of FIG. 8B. This portion represents aportion of the ECG waveform correlating to a time period surrounding asingle heart beat. For example, FIG. 9A, which shows a portion of aclean ECG waveform without any noise (e.g., when electrical stimulationis not being applied), includes only a single QRS complex. FIG. 9Billustrates how the same portion of the ECG waveform as in FIG. 9Aappears during application of electrical stimulation when the noise orinterference caused by the electrical stimulation is visible on the ECGwaveform. The stimulation spikes surrounding the QRS complex caused bythe electrical stimulation are clearly visible in FIG. 9B. FIGS. 9C and9D schematically illustrate the same portion of the example ECG waveformof FIG. 9B after blanking or decimation (FIG. 9C) and interpolation andadditional filtration (FIG. 9D) steps are performed by the denoisingsystem 405. FIG. 9C shows how the initial lead up portion of the QRScomplex can be blanked and then recreated in FIG. 9D using interpolationand additional filtering without compromising fidelity or morphology ofthe original ECG waveform.

The denoising processes and systems described herein can advantageouslyand successfully be used to denoise ECG signals not only when a heart isin normal sinus rhythm but also when the heart is experiencing abnormalheart rhythms or rates (e.g., arrhythmia, bigeminy, trigeminy, atrialfibrillation, ventricular fibrillation, tachycardia, bradycardia, etc.).Thus, accurate patient diagnoses can advantageously be made even whenthe denoising processes are being performed. For complicated heartbeats(e.g., premature ventricular contraction (PVC), bigeminy, etc.), otherECG signal manipulation may be used. Bench testing was performed toevaluate fidelity and performance of the denoising processes describedherein. Stimulation spikes were extracted from surface recordingsobtained during animal stimulation testing (e.g., using sheep animalmodels). These extracted stimulation spikes were superimposed on storedhuman ECG waveforms from a database. The original ECG waveform and thedenoised ECG waveforms after application of the denoising processesdescribed herein were compared. The denoising methods were found not tohave an appreciable impact on morphology or fidelity of the ECGwaveforms, as shown, for example in FIGS. 10A-13B. FIGS. 10B, 11B, 12Band 13B show comparisons of the original ECG waveforms and the denoisedECG waveforms for various heart rhythms. For example, the mean qualityof signal reconstruction (QSR) may be greater than or equal to 95%(greater than or equal to: 95%, 96%, 97%, 98%, 99%) for the denoised ECGwaveforms (e.g., for the entire waveform or signal, for the QRS waves,and/or for the P-T waves), where QSR is determined by the followingequation:

${QSR} = {100\%\left( {{1 - \frac{\sum\limits_{i = 1}^{N}\left( {{ECG}_{Clean} - {ECG}_{Filtered}} \right)^{2}}{\sum\limits_{i = 1}^{N}\left( {ECG}_{Clean} \right)^{2}}},} \right.}$where ECG_(Clean) is the data set prior to stimulation pulseinterference and where ECG_(Filtered) is the stimulation corrupted dataset after the denoising process 600. Tests of data sets with normalrhythms and data sets with arrhythmias including bigeminy, atrialfibrillation, and ventricular fibrillation described above resulted inQSR values between 99.16% and 99.63%.

FIGS. 10A and 10B illustrate a normal sinus rhythm ECG waveform duringapplication of neurostimulation without denoising and with denoising,respectively. As shown, the pronounced T and P waves are not impacted(or not significantly impacted) by the denoising process. The lineS_(peak) in FIG. 10B indicates the location of the original stimulationartifact, or transitory noise, spikes from FIG. 10A prior to denoising.

FIGS. 11A and 11B illustrate an ECG waveform indicative of bigeminyduring application of neurostimulation without denoising and withdenoising, respectively. Again, the line S_(peak) in FIG. 11B indicatesthe location of the original stimulation artifact, or transitory noise,spikes from FIG. 11A prior to denoising.

FIGS. 12A and 12B illustrate an ECG waveform indicative of atrialfibrillation during application of neurostimulation without denoisingand with denoising, respectively. Again, the line S_(peak) in FIG. 12Bindicates the location of the original stimulation artifact, ortransitory noise, spikes from FIG. 12A prior to denoising. FIGS. 13A and13B illustrate an ECG waveform indicative of ventricular fibrillationduring application of neurostimulation without denoising and withdenoising, respectively.

The denoising processes and systems described herein may also be used todenoise ECG signals or other bio-signals or physiological signals (e.g.,other cardiac-related signals correlated to a cardiac cycle, biophysicalsignals, blood pressure signals, respiratory rate signals, or any otherelectrical or electrochemical signal) when electromagnetic energy orpulses (e.g., electrical stimulation pulses) are applied to tissue otherthan nerves surrounding the pulmonary artery. For example, the denoisingprocesses and systems described herein may also be used to denoisesignals when other forms of tissue modulation or electrical energyapplication or other therapy is occurring or being performed (e.g.,spinal neuromodulation, pacing with a pacemaker, defibrillation with animplantable defibrillator or external defibrillation system, pulsedelectrocautery, stimulation of nerves to treat urinary or fecalincontinence, muscle stimulation, prostate stimulation, brainstimulation, stimulation of the vagus nerve, stimulation of osteoblasts,joint stimulation therapy to treat orthopedic conditions, iontophoresis,radiofrequency tissue ablation, etc.). In various implementations, thedenoising processes and systems described herein may be used to denoisemultiple waveforms or signals obtained from multiple different sources.

FIG. 14 is a front view of an example stimulation system 1400 (e.g.,neuromodulation system 410). The stimulation system 1400 comprises ahousing 1402, a catheter connector 1404 including electrical connectors1406, a display 1408, and an input button 1410 to allow a user toprovide input with respect to the display 1408. The housing 1402 cancontain stimulation electronics including a switch matrix for electrodestimulation. In some examples, a minimum output of the stimulationmatrix is 25 mA, up to 8 ms, and 100 Hz. Other minimums, maximums, andspecified parameters (e.g., number of polarities, pulsing mode,amplitude, phase, voltage, duration, inter-pulse interval, duty cycle,dwell time, sequence, waveform, etc.) are also possible. A computingdevice 1420 (e.g., networked computer terminal, desktop, laptop, tablet,smartphone, smartwatch, etc.) may be communicatively coupled to thestimulation system 1400 via wired or wireless system. The computingdevice 1420 may be the controller or control unit 412 in the schematicof FIG. 4 . In some examples, a tablet may be connected to thestimulation system 1400 via a USB connection 1422 (e.g., as shown inFIG. 14 ). The computing device 1420 may include a display (e.g.,touchscreen display) providing a graphical user interface configured toset stimulation parameters, present sensor data, view waveforms, storedata, etc. The computing device 1420 may be networked to other computingdevices, networks, the internet (e.g., via secured, HIPAA-compliantprotocol), etc. The stimulation system may also include electricalconnectors (not shown) that may be configured to interface withelectrical connectors from ECG leads (e.g., three or more leads fromskin ECG patches). The stimulation system 1400 may include additionalelectrical connectors that are not used to connect to current catheters,but that can provide the ability to update the system for futuredevelopments. The stimulation system 1400, the computing device 1420,and/or another computing device may include embedded programs forstimulation and/or sensing. The stimulation system 1400, the computingdevice 1420, and/or another computing device may include safety alarmsconfigured to alert a user at the stimulation system 1400, the computingdevice 1420, and/or another computing device of an alarm event, such asthose described herein.

In some implementations, the system comprises various features that arepresent as single features (as opposed to multiple features). Forexample, in one implementation, the system includes a single ECG device,a single denoising subsystem and a single neuromodulation subsystem. Asingle pressure sensor may also be included. The system may comprise asingle patient monitor or display as described herein. Multiple featuresor components are provided in alternate implementations.

In some implementations, the system comprises one or more of thefollowing: means for tissue modulation (e.g., an electrical stimulationsystem including a stimulation pulse generator, a catheter with one ormore electrodes and/or sensors), means for removing stimulation artifactfrom biological or physiological parameter signals or waveforms (e.g.,denoising system including one or more of an ADC, a DAC, amplifiers,multi-domain signal processing subsystems that comprise multipledifferent filters implemented in hardware and/or software), etc.

The foregoing description and examples has been set forth merely toillustrate the disclosure and are not intended as being limiting. Eachof the disclosed aspects and examples of the present disclosure may beconsidered individually or in combination with other aspects, examples,and variations of the disclosure. In addition, unless otherwisespecified, none of the steps of the methods of the present disclosureare confined to any particular order of performance. Modifications ofthe disclosed examples incorporating the spirit and substance of thedisclosure may occur to persons skilled in the art and suchmodifications are within the scope of the present disclosure.

While the methods and devices described herein may be susceptible tovarious modifications and alternative forms, specific examples thereofhave been shown in the drawings and are herein described in detail. Itshould be understood, however, that the invention is not to be limitedto the particular forms or methods disclosed, but, to the contrary, theinvention is to cover all modifications, equivalents, and alternativesfalling within the spirit and scope of the various examples describedand the appended claims. Further, the disclosure herein of anyparticular feature, aspect, method, property, characteristic, quality,attribute, element, or the like in connection with an example can beused in all other examples set forth herein. Any methods disclosedherein need not be performed in the order recited. Depending on theexample, one or more acts, events, or functions of any of thealgorithms, methods, or processes described herein can be performed in adifferent sequence, can be added, merged, or left out altogether (e.g.,not all described acts or events are necessary for the practice of thealgorithm). In some examples, acts or events can be performedconcurrently, e.g., through multi-threaded processing, interruptprocessing, or multiple processors or processor cores or on otherparallel architectures, rather than sequentially. Further, no element,feature, block, or step, or group of elements, features, blocks, orsteps, are necessary or indispensable to each example. Additionally, allpossible combinations, subcombinations, and rearrangements of systems,methods, features, elements, modules, blocks, and so forth are withinthe scope of this disclosure. The use of sequential, or time-orderedlanguage, such as “then,” “next,” “after,” “subsequently,” and the like,unless specifically stated otherwise, or otherwise understood within thecontext as used, is generally intended to facilitate the flow of thetext and is not intended to limit the sequence of operations performed.Thus, some examples may be performed using the sequence of operationsdescribed herein, while other examples may be performed following adifferent sequence of operations.

The various illustrative logical blocks, modules, processes, methods,and algorithms described in connection with the examples disclosedherein can be implemented as electronic hardware, computer software, orcombinations of both. To clearly illustrate this interchangeability ofhardware and software, various illustrative components, blocks, modules,operations, and steps have been described above generally in terms oftheir functionality. In some implementations, the modules are modulesfor processing data, wherein the module is stored in a memory. Themodule may comprise software in the form of an algorithm ormachine-readable instructions. Whether such functionality is implementedas hardware or software depends upon the particular application anddesign constraints imposed on the overall system. The describedfunctionality can be implemented in varying ways for each particularapplication, but such implementation decisions should not be interpretedas causing a departure from the scope of the disclosure.

The various illustrative logical blocks and modules described inconnection with the examples disclosed herein can be implemented orperformed by a machine, such as a general purpose processor, a digitalsignal processor (DSP), an application specific integrated circuit(ASIC), a field programmable gate array (FPGA) or other programmablelogic device, discrete gate or transistor logic, discrete hardwarecomponents, or any combination thereof designed to perform the functionsdescribed herein. A general purpose processor can be a microprocessor,but in the alternative, the processor can be a controller,microcontroller, or state machine, combinations of the same, or thelike. A processor can also be implemented as a combination of computingdevices, e.g., a combination of a DSP and a microprocessor, a pluralityof microprocessors, one or more microprocessors in conjunction with aDSP core, or any other such configuration.

The blocks, operations, or steps of a method, process, or algorithmdescribed in connection with the examples disclosed herein can beembodied directly in hardware, in a software module executed by aprocessor, or in a combination of the two. A software module can residein RAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory,registers, hard disk, a removable disk, an optical disc (e.g., CD-ROM orDVD), or any other form of volatile or non-volatile computer-readablestorage medium known in the art. A storage medium can be coupled to theprocessor such that the processor can read information from, and writeinformation to, the storage medium. In the alternative, the storagemedium can be integral to the processor. The processor and the storagemedium can reside in an ASIC. The ASIC can reside in a user terminal. Inthe alternative, the processor and the storage medium can reside asdiscrete components in a user terminal.

Conditional language used herein, such as, among others, “can,” “might,”“may,” “e.g.,” and the like, unless specifically stated otherwise, orotherwise understood within the context as used, is generally intendedto convey that some examples include, while other examples do notinclude, certain features, elements, and/or states. Thus, suchconditional language is not generally intended to imply that features,elements, blocks, and/or states are in any way required for one or moreexamples or that one or more examples necessarily include logic fordeciding, with or without author input or prompting, whether thesefeatures, elements and/or states are included or are to be performed inany particular example.

The methods disclosed herein may include certain actions taken by apractitioner; however, the methods can also include any third-partyinstruction of those actions, either expressly or by implication. Forexample, actions such as “positioning an electrode” include “instructingpositioning of an electrode.”

The ranges disclosed herein also encompass any and all overlap,sub-ranges, and combinations thereof. Language such as “up to,” “atleast,” “greater than,” “less than,” “between,” and the like includesthe number recited. Numbers preceded by a term such as “about” or“approximately” include the recited numbers and should be interpretedbased on the circumstances (e.g., as accurate as reasonably possibleunder the circumstances, for example ±5%, ±10%, ±15%, etc.). Forexample, “about 1 V” should include “1 V.” Phrases preceded by a termsuch as “substantially” include the recited phrase and should beinterpreted based on the circumstances (e.g., as much as reasonablypossible under the circumstances). For example, “substantiallyperpendicular” includes “perpendicular.” Unless stated otherwise, allmeasurements are at standard conditions including temperature andpressure. The phrase “at least one of” is intended to require at leastone item from the subsequent listing, not one type of each item fromeach item in the subsequent listing. For example, “at least one of A, B,and C” can include A, B, C, A and B, A and C, B and C, or A, B, and C.

What is claimed is:
 1. A system comprising: an electrical stimulationsystem; and a denoising system comprising circuitry configured to:receive original ECG signals from an ECG electrode array; receive asynchronization signal from the electrical stimulation system indicativeof initiation of electrical stimulation being applied by the electricalstimulation system; denoise the original ECG signals after receipt ofthe synchronization signal via one or more denoising stages, whereindenoising the original ECG signals comprises blanking portions of theoriginal ECG signals and modifying the blanked portions to providemodified ECG signals with reduced transitory noise; determine thatelectrical stimulation has been stopped based on the synchronizationsignal; and cause the original ECG signals to bypass the one or moredenoising stages upon determining that electrical stimulation hasstopped.
 2. The system of claim 1, wherein the circuitry comprises oneor more processors further configured to digitize the portions of theoriginal ECG signals.
 3. The system of claim 2, wherein the one or moreprocessors are further configured to refine the modified ECG signalsusing at least one of a linear phase filter or a digital finite impulseresponse filter to create denoised ECG signals.
 4. The system of claim3, wherein the one or more processors are further configured to: convertthe denoised ECG signals into an analog signal to facilitate output on adisplay; and output the denoised ECG signals for presentation on thedisplay.
 5. The system of claim 4, further comprising a patient monitorcomprising a display configured to display the output.
 6. The system ofclaim 1, wherein said blanking comprises temporarily removing valuesstored at memory locations corresponding to the portions of the originalECG signals and wherein said modifying the blanked portions comprisesinterpolation, and wherein said interpolation comprises identifying alast value prior to said blanking and a first value after said blankingand replacing the removed values in the memory locations withinterpolated values between the last value and the first value in thememory locations.
 7. The system of claim 6, wherein the circuitrycomprises one or more processors further configured to filter out 50 Hzor 60 Hz line frequency components for a time period prior to saidblanking and following said blanking to ensure the first value and thelast value are not affected by the 50 Hz or 60 Hz line frequencycomponents.
 8. The system of claim 1, wherein said blanking comprisestemporarily removing values stored at memory locations corresponding tothe portions of the original ECG signals and wherein said modifying theblanked portions comprises interpolation, and wherein said interpolationcomprises calculating modified values to replace the removed values inthe memory locations.
 9. The system of claim 1, wherein said blankingcomprises temporarily removing values stored at memory locationscorresponding to the portions of the original ECG signals and whereinsaid modifying the blanked portions comprises replacing the removedvalues with a last known good value prior to said blanking.
 10. Thesystem of claim 1, wherein the circuitry comprises sample and holdcircuitry.
 11. The system of claim 1, wherein the electrical stimulationsystem is a cardio pulmonary nerve stimulation system.
 12. The system ofclaim 1, further comprising one or more switches configured to open andclose based on the synchronization signal.
 13. The system of claim 1,wherein the synchronization signal is continuously delivered for aduration of the electrical stimulation.
 14. A system comprising: anelectrical stimulation system; and a denoising system comprising one ormore processors configured to, upon execution of stored instructions ona non-transitory computer-readable medium: receive one or more originalECG signals from an ECG electrode array; receive a synchronizationsignal from the electrical stimulation system indicative of initiationof electrical stimulation being applied by the electrical stimulationsystem; denoise the one or more original ECG signals after receipt ofthe synchronization signal via a denoising sub-process, whereindenoising the one or more original ECG signals comprises blankingportions of the one or more original ECG signals and modifying theblanked portions to provide one or more modified ECG signals withreduced transitory noise; output the one or more modified ECG signalsfor display; determine that electrical stimulation has been stoppedbased on the synchronization signal; and cause the one or more originalECG signals to bypass the denoising sub-process upon determining thatelectrical stimulation has stopped.
 15. The system of claim 14, furthercomprising an alert generation subsystem configured to generate an alertif a characteristic of the one or more original ECG signals is out of athreshold range.
 16. The system of claim 15, wherein the characteristicis an R-R interval between successive R waves of the one or moreoriginal ECG signals.
 17. The system of claim 14, wherein the electricalstimulation system is a cardio pulmonary nerve stimulation system. 18.The system of claim 14, further comprising one or more switchesconfigured to open and close based on the synchronization signal. 19.The system of claim 14, wherein the synchronization signal iscontinuously delivered for a duration of the electrical stimulation. 20.The system of claim 19, wherein the synchronization signal is in an “on”state when electrical stimulation is being applied and in an “off” statewhen electrical stimulation has stopped.